Effects Of Enzyme Replacement Therapy Research Articles

CRIM-negative infantile Pompe disease, long-term observation of the effect of enzyme replacement therapy: a clinical case

Background. Infantile-onset form of Pompe disease (IOPD) comprises a progressive and fatal disease in the absence of pathogenetic treatment. Enzyme replacement therapy using biologically active recombinant human alglucosidase alfa is considered as a treatment option to increase the life expectancy of patients with early diagnosis and timely initiation of therapy.Case description. A child aged 5 months was delivered to the Cardiology Department of Children’s Republican Clinical Hospital (Tatarstan, Russia) for examination and clarification of the diagnosis. The patient’s parents complained of his shortness of breath, unproductive cough, cyanosis of the nasolabial triangle when restless, weakness, lethargy during breastfeeding session, as well as decreased appetite up to refusal to eat, constantly enlarged tongue. The examination revealed macroglossia and hypersalivation, pseudohypertrophy of calf muscles, dyspnea involving the accessory muscles, hepatomegaly, diffuse muscular hypotonia. Laboratory tests revealed an increase in alanine aminotransferase level greater than four times the normal values, aspartate aminotransferase level — more than nine times, a significant rise of creatine phosphokinase and lactate dehydrogenase, as well as natriuretic peptide. Echocardiography revealed significant myocardial hypertrophy of both the left and right ventricles. Complaints, medical history, clinical examination, and all of the above changes in laboratory and instrumental examinations suggested a group of hereditary metabolic diseases (Pompe disease), confirmed by a pronounced decrease in the activity of the alpha-glucosidase enzyme to 0.12 μmol/l/h in dry blood spots with subsequent molecular genetic study and detection of compound-heterozygous mutations in the GAA gene. It was decided to initiate specific enzyme replacement therapy by intravenous administration of a recombinant form of human acidic alpha-glucosidase (alglucosidase alfa) at a dose of 20 mg/kg/injection in a frequency of once every 2 weeks. In addition, CRIM (cross-reactive immunological material)-negative status determined immune tolerance therapy, including the most studied combination of three drugs: rituximab, methotrexate, and intravenous immunoglobulin, as a response to enzyme replacement therapy. Long-term observation of the effect of enzyme replacement therapy brought positive results in the form of new motor skills, decreased content of intracellular enzymes and natriuretic peptide, reduction of myocardial hypertrophy of the left and right ventricles. In the future, the child needs lifelong treatment.Conclusion. Awareness of physicians about Pompe disease will prevent the growth in diagnostic errors and neglected cases. In case of early confirmation, the effectiveness of currently available ERT increases: the possibility to stop the disease progression, to reverse its individual clinical manifestations, and to improve the patient’s quality of life.

Exosome Secretion and Cellular Signaling Change in a Fabry Disease Cell Model Induced by Gene-silencing.

Fabry disease (FD) is caused by α-galactosidase A (AGA) deficiency, which ultimately leads to the intracellular accumulation of globotriaosylceramide (Gb3). Exosomes play a role in maintaining cellular homeostasis by clearing damaged or toxic materials, including proteins. In the process of excessive accumulation of intracellular Gb3 in Fabry disease, it may be suggested that exosomal secretion of Gb3 increases to preserve cell homeostasis. This study sought to determine how exosomal secretion and cell signaling change in an FD cell model produced by gene silencing. HEK293T cells were transfected with plasmids carrying shRNA against the GLA gene to produce the FD cell model. A recombinant AGA, agalsidase-beta, was used to evaluate the effect of enzyme replacement therapy (ERT) on exosomal secretion and cell signaling. Exosome secretion was significantly increased in the Fabry disease cell model compared to the control vector cell model, and significantly decreased after agalsidase-beta treatment. The FD cell model showed higher reactive oxygen species (ROS) production and p53 protein expression compared to the control vector cell model. Increased exosomal secretion in Fabry disease may be a cellular mechanism to avoid excessive and cytotoxic accumulation of Gb3 in lysosomes through intracellular signaling, including increased p53 expression.

Clinical phenotypes and variants of mutations of the <i>ALPL</i> gene in children with hypophosphatasia, enzyme replacement therapy with Asfotase alfa: literature and clinical case data

The article presents current literature data on clinical phenotypes and variants of ALPL gene mutations, the effectiveness of enzyme replacement therapy with asfotase alfa in children with hypophosphatasia (HPP). HPP is inherited disease ORPHA (436). The OMIM catalog contains forms of HPP: perinatal (lethal), infantile; hypophosphatasia of childhood; hypophosphatasia in adults; odontohypophosphatasia. M.E. Nunes (2023) considers 7 forms of HPP, taking into account the age and severity of the clinical manifestation. As a result of worldwide molecular genetic studies, fundamental information has been obtained on the phenotypic features of the manifestation and severity of HFF in pediatric patients, depending on the variants of the ALPL gene mutations. Molecular genetics diagnosis and enzyme replacement therapy with Asfotase alfa in our country are guaranteed for children with HPP at the expense of the «Krug Dobra Foundation», the founder of the foundation is the Ministry of Health of the Russian Federation. The article presents a clinical observation of a proband with hypophosphatasia receiving Asfotase alfa.

Abstract 16438: Effect of Enzyme Replacement Therapy on Diastolic Function in Patients With Fabry Disease

Introduction: The effects of ERT (enzyme replacement therapy) on cardiac manifestations in patients with Fabry disease (FD) are ambiguous. We aimed to investigate the response to ERT using diastolic stress echocardiography (DSE). Hypothesis: Diastolic function of FD would be improved after ERT. Methods: 19 patients with FD who underwent ERT were analyzed. All patients had DSE prior to ERT and post ERT at 1 year follow-up. We measured early diastolic (e’) velocity of the mitral annulus at baseline, 25 Watt (W) and peak exercise. The difference of diastolic reserve (ΔDR) between pre and post ERT was calculated. Diastolic reserve is defined as the change of e’ from baseline to 25W or peak of exercise in DSE. Results: Overall diastolic reserve tends to be improved (ΔDR25W: 0.66±1.36, ΔDRpeak 1.47±2.61) after 1 year of the ERT. However, there was no significant change in left ventricular (LV) wall thickness and LV mass index before and after the ERT. When patients were classified into two groups according to ΔDRpeak (Group 1, n=6, ΔDRpeak ≤0; Group 2, n=13, ΔDRpeak >0), group 2 showed more higher pre-ERT MWE (93.6±3.2 vs 84.8±5.0, p<0.01). The pre-ERT longitudinal strain of LV was better in group 2 compared to group 1 (-14.6±2.6 vs -9.9±2.3m p<0.01). LAVI (44.0±12.9 vs 25.5±8.0, p<0.01), LVEDD (50.8±2.8 vs 46.5 ± 3.0, p<0.01) and LV mass index (204.5±57.5 vs 130.4±45.6, p=0.01) of pre ERT were higher in group 1. Conclusions: Diastolic function of FD was improved generally after ERT in FD patients FD patients who have relatively preserved chamber size and mechanical function before starting ERT showed a better response to ERT. In determining the ERT effect, evaluation of diastolic function is more useful than structural evaluation in patients with Fabry cardiomyopathy.

Investigation of bone mineral density and the changes by enzyme replacement therapy in patients with Fabry disease.

Fabry disease (FD) is an inherited disorder that causes organ dysfunction. However, only a few studies have reported on bone mineral density (BMD) in FD patients, and the relationship between BMD and clinical factors such as globotriaosylsphingosine (lyso-Gb3) remains unclear. Therefore, the current study sought to investigate BMD in FD patients, the relationship between BMD and lyso-Gb3, and the effects of enzyme replacement therapy (ERT) on changes in BMD and lyso-Gb3. This single-center, observational study included 15 patients who visited our facility for FD between January 2008 and June 2021. We assessed BMD and clinical characteristics in study patients, including plasma lyso-Gb3 levels, and examined the relationship between BMD and plasma lyso-Gb3 levels, and changes in BMD after starting ERT. Male patients' BMD had reduced, whereas female patients' BMD was preserved. Male patients had significantly higher plasma lyso-Gb3 levels than female patients. Moreover, plasma lyso-Gb3 levels were found to be significantly related to the lumbar spine and femoral BMD. These were strongly linked with plasma lyso-Gb3 levels in male patients, whereas no strong link was observed in female patients. Furthermore, BMD significantly increased only in male patients although plasma lyso-Gb3 levels significantly decreased by ERT in all patients. BMD decreased possibly due to Gb3 accumulation, and ERT could increase BMD in male FD patients.

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.

Egyptian Gaucher disease type 3 patients: a large cohort study spanning two decades

BackgroundGaucher disease (GD) has been the subject of genotype/phenotype studies as well as therapeutic innovation. A cohort of ethnically homogeneous Egyptian patients suffering from GD type 3 (GD3) is described here, with the effects of enzyme replacement therapy (ERT) highlighted.MethodsWe studied the long-term outcome after 20 years of ERT in 85 patients with GD3 registered at the Pediatric Hematology Clinic of Cairo University since 1998. We obtained organ volumes, growth parameters, and neurological assessment at baseline and during ERT.ResultsOf the total sample, 77.6% of patients were diagnosed before the age of 2 years. Our patients were highly consanguineous, and 51% had a family history of GD. The most prevalent genotype was homozygous p.Leu483Pro (75.7%), followed by homozygous p.Asp448His (11%). Hemato-visceral aspects of disease included anemia (75.6%), moderate to severe thrombocytopenia (21.7%), severe splenomegaly (49.2%), and severe hepatomegaly (10.8%). One patient had liver cirrhosis with hepatopulmonary syndrome. Oculomotor apraxia, squint, and bulbar symptoms were reported in 48.6%, 30.6%, and 29.4% of patients, respectively. Imiglucerase (Cerezyme) was administered to all patients for reversal of hemato-visceral and growth parameters. The overall survival rate was 71% at 20 years; 20 patients died of pulmonary and neurological diseases.ConclusionThis is the largest single-center study of GD3 patients with predominant homozygous p.Leu483Pro genotype. The patients had a very early onset of disease and severe disease parameters. The renunciation of hemato-visceral disease was achieved effectively by ERT with 71% OS, and one third of patients developed complications.

Prenatal asfotase alfa-mediated enzyme replacement therapy restores delayed calcification in a severe infantile form of hypophosphatasia model mice

Hypophosphatasia (HPP) is a congenital disorder caused by mutations in the tissue-nonspecific alkaline phosphatase (TNALP) gene. The pathogenesis of HPP varies, ranging from severe cases in which there is total absence of fetal bone calcification, which leads to stillbirth, to relatively mild cases in which the effects are confined to the teeth, such as early loss of the primary teeth. In recent years, the establishment of enzyme supplementation as a treatment method has prolonged survival in patients; however, this approach does not provide sufficient improvement for failed calcification. Furthermore, the effects of enzyme replacement therapy on the jawbone and periodontal tissues have not yet been studied in detail. Therefore, in this study, we investigated the therapeutic effects of enzyme replacement therapy on jawbone hypocalcification in mice. Recombinant TNALP was administered to mothers before birth and newborns immediately after birth, and the effect of treatment was evaluated at 20 days of age. The treated HPP mice had improved mandible (mandibular length and bone quality) and tooth quality (root length of mandibular first molar, formation of cementum), as well as improved periodontal tissue structure (structure of periodontal ligament). Furthermore, prenatal treatment had an additional therapeutic effect on the degree of mandible and enamel calcification. These results suggest that enzyme replacement therapy is effective for the treatment of HPP, specifically in the maxillofacial region (including the teeth and mandible), and that early initiation of treatment may have additional beneficial therapeutic effects.

Long-term effectiveness of enzyme replacement therapy in Fabry disease with the p.Arg227Ter variant: Fabry disease in Ostrobothnia (FAST) study.

Fabry disease (FD) is an X chromosome-linked, life-threatening lysosomal disease caused by one of more than 1000 currently known variants in the α-galactosidase A (GLA) gene. The follow-up part of the Fabry Disease in Ostrobothnia (FAST) study reports the long-term effect of enzyme replacement therapy (ERT) on a prospectively collected cohort of 12 patients, 4 males and 8 females, mean age 46 years (SD 16), with the classical variant c.679C > T p.Arg227Ter, which is one of the most common FD variants worldwide. In the natural history period of the FAST study, half of the patients in both sexes had at least one major event, of which 80% were of cardiac origin. During 5 years of ERT, four patients had a total of six major clinical events consisting of one silent ischemic stroke, three ventricular tachycardias and two increased left ventricular mass indexes. In addition, four patients developed minor cardiac events, four patients minor renal events, and one patient a minor neurological event. ERTs may delay but not prevent the progression of the disease in most patients with the variant Arg227Ter. This variant might be suitable for investigating the efficacy of second-generation ERTs compared to the currently used ERTs regardless of sex.

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.

Long-term effectiveness of enzyme replacement therapy in Fabry disease with the p. Arg227Ter (R227*) mutation

Long-term effectiveness of enzyme replacement therapy in Fabry disease with the p. Arg227Ter (R227*) mutation

Dose-dependent effects of enzyme replacement therapy on skeletal disease progression in mucopolysaccharidosis VII dogs

Mucopolysaccharidosis (MPS) VII is an inherited lysosomal storage disorder characterized by deficient activity of the enzyme β-glucuronidase. Skeletal abnormalities are common in patients and result in diminished quality of life. Enzyme replacement therapy (ERT) for MPS VII using recombinant human β-glucuronidase (vestronidase alfa) was recently approved for use in patients; however, to date there have been no studies evaluating therapeutic efficacy in a large animal model of MPS VII. The objective of this study was to establish the effects of intravenous ERT, administered at either the standard clinical dose (4mg/kg) or a high dose (20mg/kg), on skeletal disease progression in MPS VII using the naturally occurring canine model. Untreated MPS VII animals exhibited progressive synovial joint and vertebral bone disease and were no longer ambulatory by age 6months. Standard-dose ERT-treated animals exhibited modest attenuation of joint disease, but by age 6months were no longer ambulatory. High-dose ERT-treated animals exhibited marked attenuation of joint disease, and all were still ambulatory by age 6months. Vertebral bone disease was recalcitrant to ERT irrespective of dose. Overall, our findings indicate that ERT administered at higher doses results in significantly improved skeletal disease outcomes in MPS VII dogs.

Cardiac involvement in Fabry disease - A non-invasive assessment and the role of specific therapies.

Fabry disease is an X-linked inherited metabolic disorder due to the pathogenic mutation of the GLA gene, which codes lysosomal enzyme alpha-galactosidase A. The resultant accumulation of glycosphingolipids causes various systemic symptoms in childhood and adolescence, and major organ damage in adulthood. Cardiac involvement is important as the most frequent cause of death in Fabry disease patients. Progressive left ventricular hypertrophy with varying degrees of contractile dysfunction as well as conduction abnormalities and arrhythmias are typical cardiac features, and these findings can be evaluated in detail via non-invasive modalities, such as an electrocardiogram, echocardiography and cardiac magnetic resonance. In addition, specific therapies of enzyme replacement therapy and pharmacological chaperone therapy are available, and their beneficial effects on cardiac involvement have been reported. This minireview highlights recent evidence concerning non-invasive modalities for assessing cardiac involvement in Fabry disease and the effects of enzyme replacement therapy and pharmacological chaperone therapy on the findings of those modalities.

The Role of Liver Function Tests in Monitoring the effect of Enzyme Replacement Therapy in Children with Gaucher Disease

Background: Gaucher disease (GD) is an autosomal recessive hereditary disease. The etiology, pathophysiology, diagnosis, and prognosis of GD in children might all be affected by a variety of biomarkers. The majority of them are linked to abnormalities caused by this lysosomal storage disorder, which is caused by a deficiency of the glucocerebrosidase enzyme that affects numerous organs including the liver, spleen, and bones. Objectives: to investigate the relevance of liver function tests in the assessment of treatment response in children with Gaucher's disease who are undergoing enzyme replacement therapy in a follow-up manner. Methods: A case-control study was performed on 67 children (girls and boys) with GD who were recruited from the Children Welfare Hospital Consultation Clinic, the Gastroenterology and Hepatology Teaching Hospital, and the Central Child's Teaching Hospital. The levels of ALT, AST, total bilirubin (TB), and total protein (TP) were assessed in the samples of 67 Gaucher children, who were classified as recently diagnosed untreated patients (n=9), patients who received ERT for 3-6 months (n=18), 6-12 months (n=20), and patients who received ERT for more than one year (n=20), and compared to twenty newly comparable age-matched controls. The practical part of the study was conducted at research laboratories in the College of Pharmacy, Al-Maaql University and the Department of Pharmacy, Al-Turath University College during the period from December 2020 to March 2021. Results: The results showed that total protein levels in patients were significantly lower than in age-matched control group. The negative significant correlations between the levels of AST, ALT, and TB with the period of receiving treatment and the positive significant correlations between the levels of total protein and the period of receiving treatment indicated that the studied parameters were significantly associated with the period of receiving ERT. The effect of ERT was also indicated by the results of the ANOVA test, which revealed significant variations in the levels of ALT, AST, total bilirubin, and total protein across the patient subgroups. Conclusions: ALT, AST, total bilirubin, and total protein have been shown to have diagnostic significance in newly diagnosed untreated children with a wide range of treatment responses, limiting their utility in treatment monitoring.

Renoprotective Effect of Agalsidase Alfa: A Long-Term Follow-Up of Patients with Fabry Disease.

Fabry disease is a rare lysosomal storage disorder caused by mutations in the GLA gene, which, without treatment, can cause significant renal dysfunction. We evaluated the effects of enzyme replacement therapy with agalsidase alfa on renal decline in patients with Fabry disease using data from the Fabry Outcome Survey (FOS) registry. Male patients with Fabry disease aged >16 years at agalsidase alfa start were stratified by low (≤0.5 g/24 h) or high (>0.5 g/24 h) baseline proteinuria and by ‘classic’ or ‘non-classic’ phenotype. Overall, 193 male patients with low (n = 135) or high (n = 58) baseline proteinuria were evaluated. Compared with patients with low baseline proteinuria, those with high baseline proteinuria had a lower mean ± standard deviation baseline eGFR (89.1 ± 26.2 vs. 106.6 ± 21.8 mL/min/1.73 m2) and faster mean ± standard error eGFR decline (−3.62 ± 0.42 vs. −1.61 ± 0.28 mL/min/1.73 m2 per year; p < 0.0001). Patients with classic Fabry disease had similar rates of eGFR decline irrespective of baseline proteinuria; only one patient with non-classic Fabry disease had high baseline proteinuria, preventing meaningful comparisons between groups. In this analysis, baseline proteinuria significantly impacted the rate of eGFR decline in the overall population, suggesting that early treatment with good proteinuria control may be associated with renoprotective effects.

Effects of Enzyme Replacement Therapy on Quality of Life, Functional Independence and Aerobic Capacity in Children with Mucopolysaccharidosis

: The mucopolysaccharidosis (MPS) can lead to poor endurance and mobility, often associated with pain, restricted range of motion (ROM), low energy levels and fatigue, negatively affecting quality of life and activities of daily living. This study aimed to examine the impact of enzyme replacement therapy (ERT) on aerobic capacity, functional independence and quality of life in children with MPS and to determine the anxiety and depression levels of their caregivers. Study Design established in Cross sectional study. Twelve children aged 3 to 11 years were included in the study. The subjects were divided into two groups according to the use of ERT. Quality of life and functional independence were assessed using the Pediatric Quality of Life Inventory (PedsQL) and Functional Independence Measure for Children (WeeFIM). The 6-minute walk test (6MWT) and timed up and go test (TUG) were used to evaluate aerobic capacity. Anxiety and depression levels of parents were assessed using the Beck Anxiety Inventory (BAI) and Beck Depression Inventory (BDI), respectively. A total of 12 MPS patients 7 boys (58.3%) and 5 girls (41.7%) with a mean age of 5.58±2.67 years were included in the study.1 patient had MPS type I, 2 patients had MPS type III, 5 patients had MPS type IV, and 4 patients had MPS type VI. Six patients were receiving ERT. The children had a mean 6MWT score of 330.83±114.29, a mean TUG score of 14.24±5.71 sec, a mean PedsQL score of 46.83±14.03 and a mean WeeFIM score of 70.83±26.85. Their caregivers had a mean BAI score of 19.25±10.95 and a mean BDI score of 19.41±6.81. A significant difference was found between the children receiving ERT and those not receiving in the WeeFIM scores (P0.05). ERT did not change aerobic capacity and quality of children with MPS but increased their level of functional independence. Multisystem involvement in MPS children may affect anxiety and depression levels of their caregivers but ERT does not seem to have any effect on this psychosocial aspect.

Clinical characteristics and effects of enzyme replacement therapy with elosulfase alfa in Korean patients with mucopolysaccharidosis type IVA

Mucopolysaccharidosis type IVA (MPS IVA) is a rare autosomal recessive disorder caused by a deficiency in N-acetylgalactosamine-6-sulfatase, which results in skeletal and connective tissue abnormalities, as well as various non-skeletal manifestations. Although enzyme replacement therapy (ERT) is recommended as the first-line treatment, the outcomes of ERT on bone pathology remain controversial. We report clinical characteristics and outcomes of ERT in 9 patients with MPS IVA (6 males and 3 females) from 7 unrelated families. During ERT, results from pulmonary function tests, echocardiography, the 6-min walk test, and the Functional Independence Measure were monitored biannually. Anthropometric data were compared with previously reported growth charts of subjects with MPS IVA.Among the 9 patients (5 severe, and 4 slowly progressive form), 7 patients (5 severe, 2 slowly progressive) commenced ERT at a median age of 3.8 years (range: 0.8–13.7 years) and were treated for a median duration of 1.9 years (range: 1.2–5.7 years). Mean height standard deviation scores using MPS IVA growth charts were + 0.4 (+0.0 in severe phenotypes) at initiation and + 0.7 (+0.2 in severe phenotypes) at the last follow-up. Four patients with severe phenotypes underwent surgery for cervical myelopathy and 1 patient with a slowly progressive phenotype underwent a bilateral pelvic osteotomy for hip pain during ERT. The parameters of pulmonary and heart function, endurance, and Functional Independence Measure scores were maintained or increased after ERT. Overall, ERT was well tolerated without deterioration of cardiorespiratory and functional outcomes during treatment, although skeletal outcomes, including growth, were limited.

Pulmonary manifestations and the effectiveness of enzyme replacement therapy in Fabry Disease with the p. Arg227Ter (p.R227*) mutation.

BackgroundFabry disease (FD) is caused by a defect in α‐galactosidase A gene (GLA) which leads to a progressive accumulation of neutral shingolipids, mainly globotriaosylceramide and its metabolites in several organs. Pulmonary manifestations of FD mimic chronic obstructive pulmonary disease and are disproportionate to smoking status. The effect of enzyme replacement therapy (ERT) on pulmonary function is inconclusive.We studied the effect of ERT on pulmonary function in FD with a mutation p. Arg227Ter (p.R227*) which is one of the most common mutations causing classical FD in Finland and worldwide.MethodsPatients were annually examined by multidisciplinary team. Based on the maximal pulmonary oxygen consumption at the baseline, either cardiopulmonary exercise test or combination of spirometry and 6‐minute walking test were performed annually during 5‐year follow‐up.ResultsFour males and eight females met the criteria for ERT and were included in this study. Three of 12 patients had obstruction by GOLD criterion before ERT, and one had a borderline obstruction. In 5 years, five patients were classified as obstructive, although the real change in FEV1/FVC was unchanged in the whole cohort. Only one patient was an active smoker.ConclusionIn nonsmokers, pulmonary manifestations in classical FD are mild and might be stabilized by ERT.

Effects of enzyme replacement therapy on cardiac function and structure in classic infantile Pompe disease: Up to 22 years of follow-up

Effects of enzyme replacement therapy on cardiac function and structure in classic infantile Pompe disease: Up to 22 years of follow-up

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.