Receiving Enzyme Replacement Therapy Research Articles

Assessing the Role of Anti rh-GAA in Modulating Response to ERT in a Late-Onset Pompe Disease Cohort from the Italian GSDII Study Group.

Patients with late-onset Pompe disease (LOPD) receiving enzyme replacement therapy (ERT) may develop IgG antibodies against alglucosidase alpha (anti-rhGAA) in the first 3months of treatment. The exact role of these antibodies in modulating efficacy of ERT in this group of patients is still not fully understood. To assess whether anti rh-GAA antibodies interfere with ERT efficacy, we studied a large Italian cohort of LOPD patients. We analyzed clinical findings and performed serial measurements of IgG anti rh-GAA antibody titers from 64 LOPD patients treated with ERT. The first examination (T0) was completed on average at 17.56months after starting ERT, while the follow-up (T1) was collected on average at 38.5months. Differences in T0-T1 delta of the six-minute walking test (6MWT), MRC sum score (MRC), gait, stairs and chair performance (GSGC) and forced vital capacity (FVC) were considered and then related to the antibody titers. Almost 22% of the patients never developed antibodies against GAA, while 78.1% had a positive titer (31.2% patients developed a low titer, 43.8% a medium titer and 3.1% a high titer). No statistical significance was found in relating the T0-T1 delta differences and antibody titers, except for MRC sum score values in a subgroup of patients treated < 36months, in which those with a null antibody titer showed a greater clinical improvement than patients with a positive titer. Our results confirm that in a large cohort of LOPD patients, anti rh-GAA antibody generation did not significantly affect either clinical outcome or ERT efficacy. However, in the first 36months of treatment, a possible interference of low-medium antibody titers with the clinical status could be present. Therefore, a careful and regular evaluation of antibody titers, especially in cases with evidence of clinical decline despite ERT, should be performed.

Clinical profile of women diagnosed with Fabry disease non receiving enzyme replacement therapy

Introduction and objectiveFabry disease (FD) is an X-linked lysosomal storage disorder due to a deficiency of the α-galactosidase A enzyme. Although women were historically considered only carriers, many studies have contradicted this fact. The main aim of this work was to set the first Spanish study out of the on-going registries on health status and management of women diagnosed with FD who were not receiving enzyme replacement therapy (ERT). Material and methodsAn epidemiological, cross-sectional, descriptive and multicentre study was assessed in women diagnosed for FD who were not receiving ERT. Assessments on symptomatology and severity were collected using several clinical questionnaires. Additionally, clinical information and lab tests were obtained from clinical records. ResultsThirty-three women with a mean age of 45.6±16.2 years were studied. Symptom onset was at a median age of 35.5 years old (range: 30.0–51.5), being diagnosed a median of 2 years later (range: 1.0–1.5). Missense mutations were the most prevalent mutation (n=22, 68.8%). Although 69% considered themselves as asymptomatic, 22 (66.7%) showed at least one FD-related clinical symptom. Using Mainz Severity Score index and Fabry International Prognosis Index neurological symptomatology obtained higher scores both for severity and prognostic. The EQ-5D questionnaire showed 42.2% patients referring to some anxiety or depression, and 30.3% thought that their life was somehow altered by the pain. 62.5% were not receiving any treatment and ERT was offered only to one patient (3.6%) who refused it. ConclusionsAlthough most of the heterozygous women for FD had not received ERT or either symptomatic treatment, they present symptoms of disease. Careful follow-up of female patients or some adjuvant treatment may be considered to delay progressive organ damage and improve patient quality of life.

The association of epicardial fat thickness and disease severity among Fabry patients

Aim: Patients with Fabry disease frequently die due to cardiovascular causes. There are numerous findings of cardiovascular involvement in patients with Fabry disease. Epicardial fat thickness is a surrogate for various cardiovascular diseases. In this study, we evaluated epicardial fat thickness and parameters of diastolic dysfunction among Fabry patients as a possible indicator of disease severity.Materials and Methods: We enrolled 14 patients with Fabry disease who receive enzyme replacement therapy. Detailed echocardiographic examination was performed including diastolic functions and measurement of epicardial fat thickness. Disease severity was assessed using DS3 scoring system. Based on DS3 scores, patients are grouped into mild (10 points), moderate (10-28 points) and severe (29-32 points) disease.Results: There were two female and twelve male patients with Fabry disease. Patients were classified into three groups based on DS3 scores. Epicardial fat thickness was significantly increased among patients with advanced disease compared to patients with mild disease (p:0.002). Also, epicardial fat thickness had significant positive correlation with average E/E’ ratio (p:0.014), left atrial volume (p:0.004) and left atrial volume index (p:0.022).Conclusion: Epicardial fat thickness seems as a promising new marker of disease severity among patients with Fabry disease.Keywords: Fabry’s disease; inflammation; echocardiography.

Urinary excretion profile of microRNAs related to renal fibrosis in Fabry disease patients. A pilot study

Irreversible renal histological lesions, including glomerulosclerosis and tubulo-interstitial fibrosis, have been described in asymptomatic Fabry disease (FD) patients with normal estimated glomerular filtration rate (eGFR) and mild or absent proteinuria. However, it is currently recommended to start FD treatment in presence of clinical manifestations. During renal fibrosis miR-21, miR-192, and miR-433 that promote fibrosis are activated by TGF-β, and miR-29 and miR-200 that suppress fibrosis, are inhibited by TGF-β. The aim of this work is to compare the urinary excretion of microRNAs related to renal fibrosis in FD patients with healthy subjects. In addition, the microRNAs urinary excretion was related to study population clinical variables. Results: 24 FD patients and 10 healthy subjects of similar characteristics were compared. Asymptomatic FD women with normal α-galactosidase-A (α-gal-A) enzyme activity and symptomatic FD women with normal α-gal-A enzyme activity, who were receiving enzyme replacement therapy (ERT) presented a microRNAs urinary profile excretion similar to controls. Asymptomatic FD men or women patients with decreased α-gal-A enzyme activity presented significant differences in miR-29 (p = 0.0478) and miR-200 (p = 0.0426) compared with controls. Symptomatic FD men with decreased α-gal-A enzymatic activity, who were receiving ERT presented significant differences in miR-200 (p = 0.0238) compared with controls. Conclusion: In asymptomatic FD patients with decreased α-gal-A enzymatic activity a microRNA profile indicative of renal fibrosis was found. These patients, at present, are not treated because they do not present clinical criteria to start ERT. In this population, the microRNAs urinary profile excretion could be useful to detect renal fibrosis in early stages.

Overview of Lysosomal Storage Diseases in Kurdistan Region/ Iraq

Background and objectives:The lysosomal lipid storage diseases are diverse disorders each due to an inherited deficiency of a lysosomal hydrolase enzyme leading to the intralysosomal accumulation of the enzyme’s particular substrate; each catabolic step, with the exception of the catabolism of lactosylceramide, has a genetically determined metabolic defect and a resultant disease. The objective of this study was to have a better review of these diseases’ burden in the region. Methods:A data of 37 patients were collected from 2013 to 2017 in the cities of the region, namely (Sulaimany, Erbil, Duhok, and Kirkuk) retrospectively through establishing a questionnaire distributed to the families of patients in whom the disease was established, and diagnosis was settled, and treatment already initiated to the patients. Results: Gaucher and Mucopolysaccharidosis were equally the commonest (17 patients, 45.9%), lysosomal storage diseases were found to be more common in males (59.4%), and more in Kurdish descendants (75.7%). most patients were from Duhok city (43.2%). Consanguinity was positive in (83.8%) of patient’s parents. Twenty-four patients (64.9%) of overall lysosomal storage disease were receiving enzyme replacement therapy. Among patients receiving treatment; 20 (83.3%) had showed improvement in their condition, compared to none 0% of patients who did not receive treatment. abdominal distention was the most common first presenting complaint in lysosomal storage diseases (10 patients, 27%). Conclusions:Lysosomal storage diseases are more common in consanguine marriage and will respond well to enzyme replacement therapy if regularly provided, it will decrease mortality and morbidity due to the disease.

Retrospective Analysis of Whole-Body Magnetic Resonance Imaging of Bone Manifestations in Long-Term Treated Patients with Gaucher Disease Type 1.

We retrospectively assessed bone and visceral manifestations in patients with Gaucher disease type 1 (GD1) with whole-body magnetic resonance imaging (WB-MRI) to determine the effects of different timing in initiating long-term enzyme replacement therapy. In 17 patients with GD1, we performed 2 WB-MRI examinations at a median interval of 13 months. Patients had received enzyme replacement therapy with alglucerase/imiglucerase for a median of 13 years prior to the first examination. MRI results were retrospectively stratified based on treatment initiation into 2 groups: "early" (age ≤12 years, median 5 years) and "late" (during adulthood, median 32 years). We evaluated occurrence of irreversible avascular necroses (AVN) and applied several semi-quantitative scores, including the Bone-Marrow-Burden (BMB) score, the Düsseldorf-Gaucher score (DGS), the Vertebra-Disc-Ratio (VDR), and the Gaucher disease type 1 Severity Scoring System (GD-DS3). MRI assessments showed no AVN in the "early" group. AVN were observed in 2 patients of the "late" group; one also had a splenic Gaucheroma. The follow-up examinations showed slight improvements in the BMB-score, DGS, and VDR, with similar tendencies in both treatment groups. The GD-DS3 score only improved in "late" group. This retrospective study supported the ongoing clinical value of enzyme replacement therapy with alglucerase/imiglucerase, as WB-MRI-based scores stayed constant or slightly improved even after long-term treatment. Secondary complications were only observed in the late treatment group. Our results suggest that "early initiation" of enzyme replacement therapy may protect the bone.

Serum cobalamin and folate as prognostic factors in canine exocrine pancreatic insufficiency: An observational cohort study of 299 dogs

Exocrine pancreatic insufficiency (EPI) in dogs is a gastrointestinal condition leading to a severe impairment of nutrient absorption. The disease is frequently associated with vitamin disturbances especially regarding cobalamin and folate. Dogs with EPI need daily expensive supportive treatment. The aim of the present study was to identify prognostic factors for EPI in dogs, through a long-term survival study of 299 dogs, taking into account epidemiological, clinical, biological and therapeutic data, with particular emphasis on serum cobalamin and folate concentration.The prevalence of low serum cobalamin (cobalamin<350ng/L) and high serum folate (folate>12μg/L) concentrations were 67% (200/299) and 55% (164/299), respectively. Dogs with hypocobalaminemia at diagnosis were significantly older than those with serum cobalamin concentration within the reference interval (P<0.001). Hypocobalaminemia at diagnosis (P=0.04), male sex (P=0.01), decreased appetite at diagnosis (P=0.008) and not receiving enzyme replacement therapy (P=0.003) were significant and independent risk factors for decreased survival in EPI. In contrast, hyperfolatemia was associated with improved prognosis (P=0.02). These results confirm the importance of measuring serum cobalamin and folate concentrations at the time EPI is diagnosed, as hypocobalaminemia is negatively associated with prognosis, particularly in the absence of a high serum folate concentration.

The relationships between urinary glycosaminoglycan levels and phenotypes of mucopolysaccharidoses.

BackgroundThe aim of this study was to use the liquid chromatography/tandem mass spectrometry (LC‐MS/MS) method to quantitate levels of three urinary glycosaminoglycans (GAGs; dermatan sulfate [DS], heparan sulfate [HS], and keratan sulfate [KS]) to help make a correct diagnosis of mucopolysaccharidosis (MPS).MethodsWe analyzed the relationships between phenotypes and levels of urinary GAGs of 79 patients with different types of MPS.ResultsThe patients with mental retardation (n = 21) had significantly higher levels of HS than those without mental retardation (n = 58; 328.8 vs. 3.2 μg/ml, p < 0.001). The DS levels in the patients with hernia, hepatosplenomegaly, claw hands, coarse face, valvular heart disease, and joint stiffness were higher than those without. Twenty patients received enzyme replacement therapy (ERT) for 1–12.3 years. After ERT, the KS level decreased by 90% in the patients with MPS IVA compared to a 31% decrease in the change of dimethylmethylene blue (DMB) ratio. The DS level decreased by 79% after ERT in the patients with MPS VI compared to a 66% decrease in the change of DMB ratio.ConclusionsThe measurement of GAG fractionation biomarkers using the LC‐MS/MS method is a more sensitive and reliable tool than the DMB ratio for MPS high‐risk screening, diagnosis, subclass identification, and monitoring the efficacy of ERT.

Consensus approach for the management of severe combined immune deficiency caused by adenosine deaminase deficiency

Inherited defects in adenosine deaminase (ADA) cause a subtype of severe combined immunodeficiency (SCID) known as severe combined immune deficiency caused by adenosine deaminase defects (ADA-SCID). Most affected infants can receive a diagnosis while still asymptomatic by using an SCID newborn screening test, allowing early initiation of therapy. We review the evidence currently available and propose a consensus management strategy. In addition to treatment of the immune deficiency seen in patients with ADA-SCID, patients should be followed for specific noninfectious respiratory, neurological, and biochemical complications associated with ADA deficiency. All patients should initially receive enzyme replacement therapy (ERT), followed by definitive treatment with either of 2 equal first-line options. If an HLA-matched sibling donor or HLA-matched family donor is available, allogeneic hematopoietic stem cell transplantation (HSCT) should be pursued. The excellent safety and efficacy observed in more than 100 patients with ADA-SCID who received gammaretrovirus- or lentivirus-mediated autologous hematopoietic stem cell gene therapy (HSC-GT) since 2000 now positions HSC-GT as an equal alternative. If HLA-matched sibling donor/HLA-matched family donor HSCT or HSC-GT are not available or have failed, ERT can be continued or reinstituted, and HSCT with alternative donors should be considered. The outcomes of novel HSCT, ERT, and HSC-GT strategies should be evaluated prospectively in "real-life" conditions to further inform these management guidelines.

Healthcare resource utilization in the management of hypophosphatasia in three patients displaying a spectrum of manifestations

BackgroundHypophosphatasia (HPP) is a rare, heterogeneous disease caused by low tissue-nonspecific alkaline phosphatase activity and associated with a range of signs and symptoms, including bone mineralization defects, respiratory problems, seizures, premature tooth loss, and fractures. Data from patients with HPP and their healthcare resource utilization are lacking. We evaluated healthcare utilization for 3 patients with differing severities of HPP.ResultsPatient 1 had perinatal HPP (received enzyme replacement therapy asfotase alfa under a compassionate use program), Patient 2 had infantile HPP, and Patient 3 had childhood HPP. Healthcare resources used in the National Health Service, England, were identified from coded activities in the hospital database and detailed medical records. These data showed that healthcare utilization was directly related to disease severity. Patient 1 had respiratory complications necessitating prolonged admission for ventilation from birth. Over 2.5 years, this patient was hospitalized 725 days, with visits from 16 specialists. Patient 2 had HPP-associated signs and symptoms starting in infancy, was treated for craniosynostosis, experienced multiple fractures, and required outpatient management for > 18 years. Patient 3 developed signs and symptoms of HPP in childhood and received outpatient and day case treatment for dental, orthopedic, and cardiovascular problems over 24 years. Healthcare utilization varied with severity and complexity of disease manifestations between these patients.ConclusionsWith the recent approval of asfotase alfa for HPP, data from this analysis may help mobilize multidisciplinary healthcare resources for management of HPP by elucidating healthcare resource needs of patients who show a spectrum of clinical manifestations of HPP.

THE EFFECT OF THE ENZYME REPLACEMENT THERAPY ON THE KIDNEY FUNCTION TESTS AND SERUM ELECTROLYTE LEVELS IN CHILDREN WITH GAUCHER DISEASE

Background: Gaucher disease (GD) is an inherited autosomal recessive disease. It is most common in the Ashkenazi Jewish population. Many biomarkers might be involved in the etiology, pathogenesis, diagnosis and prognosis of GD in children. Most of them are related to complications due to an involvement of many organs such as liver, spleen and bones by this lysosomal storage disease that caused by a lack of the enzyme glucocerebrosidase. Objective: To investigate the role of kidney function test and electrolytes (urea, creatinine, sodium and potassium) level in the monitoring of the response for the treatment used for patients with GD in follow-up manner. Methods: A case control study was done on 67 children (32 males &amp; 35 females), age range from 2-14 years (mean±SD; 5.3±2.9). The levels of sodium, potassium, urea and creatinine were measured in the samples of patients who were categorized as newly diagnosed untreated patients (n=9), patients receiving enzyme replacement therapy (ERT) for 3-6 months (n=18), 6-12 months (n=20) and patients receiving ERT for more than one year (n=20) and compared with twenty age-matched control subjects (9 males &amp; 11 females) age range from 2-14 years (mean±SD; 5.55±3.05). Results: The data indicated that the level of urea in GD patients (23.39±4.71 mg/dl) was significantly higher than that of age-matched controls (17.5±3.05 mg/dl). Non-significant differences were illustrated in the levels of sodium, potassium and creatinine. Negative significant (p&lt;0.05) correlations were obtained between the levels of urea (r= -0.752; p&lt;0.001) and creatinine (r= -0.536; p&lt;0.001) with the period of receiving ERT. Additionally, ANOVA test also revealed significant (p&lt;0.05) differences among the patients' subgroups in the levels of urea and creatinine. Results obtained from Receiver Operating Characteristic (ROC) curve revealed that urea and creatinine showed a high area under the curve (AUC), sensitivity and specificity (0.939, 77.8% and 85% for urea and 0.978, 100% and 80% for creatinine respectively) in newly diagnosed GD patients in a comparison with control. Conclusion: The possibility of using urea and creatinine in the diagnosis and monitoring the effect of ERT on the GD patients. Keywords: Gaucher disease, macrophage, renal function test, urea, creatinine, sodium, potassium, enzyme replacement therapy, imiglucerase, β-glucocerebrosidase, glucocerebroside Citation: Abdulhussein HA, Al-Obaidi FH, Arif HS. The effect of the enzyme replacement therapy on the kidney function tests and serum electrolyte levels in children with Gaucher disease. Iraqi JMS. 2018; 16(2): 182-190. doi: 10.22578/IJMS.16.2.10

Left ventricular assessment in patients with mucopolysaccharidosis using conventional echocardiography and myocardial deformation by two-dimensional speckle-tracking method

ObjectiveMucopolysaccharidosis is a rare genetic disease characterized by the intralysosomal deposition of glycosaminoglycans. Cardiovascular impairment is a common feature. Cardiac signs and symptoms are underestimated due to the disease involvement in other organs. Enzyme replacement therapy can be used in mucopolysaccharidosis I, II, IV, and VI. Thus, the knowledge about the use of new echocardiography tools is relevant to improve the care of this population. This study aimed to describe left ventricular function assessment by conventional echocardiography and left ventricular global longitudinal strain analysis and compare the alterations in patients receiving enzyme replacement therapy and who had different ages at the start of therapy. MethodOutpatient-based descriptive study. The patients were submitted to conventional echocardiography and left ventricular global longitudinal strain measurement. ResultsSixteen patients were evaluated; median age of 14.2 years (SD=5.2 years). Left ventricular hypertrophy was found in nine patients (56.2%). All patients had preserved left ventricular systolic function (Simpson and Teichholz). Nine (56.2%) patients showed alterations in left ventricular global longitudinal strain. The study showed a positive association between left ventricular hypertrophy and alteration in the left ventricular global longitudinal strain, and late start of enzyme replacement therapy and alteration in the left ventricular global longitudinal strain. ConclusionEchocardiographic alterations in patients with mucopolysaccharidosis were frequently observed, especially alterations in the left ventricular geometry and subclinical dysfunction. Patients who had a late enzyme replacement therapy start showed an association with worse left ventricular global longitudinal strain values, reinforcing the need for early diagnosis and treatment. The use of new echocardiographic tools may improve the follow-up of these patients.

Outcome of strabismus surgery in patients of type 3 gaucher’s disease

Purpose Surgical correction of esotropia in patients of neuronopathic Gaucher’s disease (GD) type 3 aiming to improve the cosmetic appearance with the evaluation of the success rate, presence of residual angle, or recurrence during the follow-up period. Study design A retrospective, descriptive study. Patients and methods Ten patients with type 3 neuronopathic GD were referred from the Pediatric Gastroenterology and Neurology Units of Mansoura Children’s Hospital. All patients suffered from systemic, neurological, and ophthalmological manifestations such as hepatosplenomegaly, horizontal gaze palsy and esotropia, respectively. They received enzyme replacement therapy, and showed a stationary course for at least 1 year before strabismus surgery. Patients were admitted and operated for cosmetic correction of esotropia. They were followed up regularly every month for 1 year. Postoperative data were recorded at the end of 1, 3, 6, and 12 months. Results In all, 80% of cases showed improvement of the angle. Orthotropia (within 10 pd) was obtained at the end of 6 months and maintained till the end of 1 year postoperatively; 20% of the cases showed residual esotropia. Conclusion Surgical correction of strabismus in type 3 GD can achieve good cosmetic results with low risk of residual angle or recurrence.

Health-related quality of life in children and adolescents living with Gaucher disease and their parents

ABSTRACTObjective: The health-related quality of life (HRQoL), clinical status and perceived burden of disease in children and adolescents with Gaucher Disease (GD) were assessed.Method: A Spanish multicenter collaboration study involving 13 hospitals was performed to evaluate pediatric patients with GD (n = 17, ages 5–18; n = 3, ages 2–4) and their parents (n = 20) using a HRQoL measure (PedsQL 4.0) and a survey on the perceived burden of the disease. Three children under five years old were evaluated by parent proxy-report. Relevant medical and socio-demographical characteristics were recorded.Results: Sixty-nine percent of the participants with GD had mild and 31% had moderate severity level, all receiving enzyme replacement therapy (ERT). HRQoL was associated with the severity score index and was adjusted for age. Age was related to school functioning (older patients had lower scores), and female patients reported worse school functioning than males. Symptoms such as bone, joint or abdominal pain, bleeding, and fatigue were negatively associated with HRQoL. Perceptions of the burden related to GD, such as feeling ill and feeling sad, were negatively associated with HRQoL. Although the PedsQL scores of children and parents showed concordance, patterns of association between symptoms and perceived burden differed between children and parents. No associations were observed between HRQoL scores and time on ERT or ERT dosage.Conclusion: HRQoL perceptions were affected by clinical status, observable and subjective symptoms, feelings of burden related to the disease, and patient characteristics (e.g. age and gender). Aspects of the disease that affect HRQoL may be perceived differently by children and parents.

Results of Fabry Disease Screening in Male Pre-End Stage Renal Disease Patients with Unknown Etiology Found Through the Platform of a Chronic Kidney Disease Education Program in a Northern Taiwan Medical Center

Background/Aims: Fabry disease (FD), a rare x-lined genetic disorder is a cause of renal deterioration. The phenotype of FD is highly variable and nonspecific, and correct diagnosis has always been delayed. We aimed to explore the prevalence and clinical presentation of FD in this high-risk male population in a Northern Taiwan medical center. Methods: This is the first study to survey the incidence of FD in this high-risk population through the platform of a chronic kidney disease (CKD) education program in Asia. A total of 1,012 male patients with unknown CKD causes were screened using an assay of alpha-galactosidase A activity (α-Gal A) by dried blood spots (DBS). A final GLA gene analysis was also done for those with low enzyme activity. Results: We identified two new patients with classic FD and four patients with late-onset FD. One novel GLA mutation with c.413 G>A was found in one classic FD patient (index 5). The prevalence of FD is about 0.59 % (6 in 1,012) in the high-risk population group with CKD. The clinical symptoms of FD patients are nonspecific except in those with various degrees of renal failure. Those patients’ correct diagnosis was delayed, taking years and even decades. Three patients received enzyme replacement therapy and one started regular hemodialysis due to persistent renal function deterioration. Another two patients were found from family screening through a new index. In addition, a false negative result occurred in one patient who was proved to have FD by his kidney pathology as determined by this screening. Conclusion: FD is not such as rare a disease and its prevalence is greater in this high-risk male population. Clinicians need to be aware that FD should be included in the differential diagnosis in CKD with unknown etiology.

Ten-year-long enzyme replacement therapy shows a poor effect in alleviating giant leg ulcers in a male with Fabry disease

Fabry disease is an X-linked lysosomal storage disorder caused by a deficiency of α-galactosidase A (α-gal A), leading to the progressive accumulation of glycosphingolipids. Classical hemizygous males usually present symptoms, including pain and paresthesia in the extremities, angiokeratoma, hypo- or anhidrosis, abdominal pain, cornea verticillata, early stroke, tinnitus, and/or hearing loss, during early childhood or adolescence. Moreover, proteinuria, renal impairment, and cardiac hypertrophy can appear with age. Enzyme replacement is the most common therapy for Fabry disease at present which has been approved in Japan since 2004. We report a case involving a 27-year-old male with extreme terminal pain, anhidrosis, abdominal pain, tinnitus, hearing impairment, cornea verticillata, and recurrent huge ulcers in the lower extremities. At the age of 16years, he was diagnosed with Fabry disease with a positive family history and very low α-gal A activity. He then received enzyme replacement therapy (ERT) with recombinant human agalsidase beta at 1mg/kg every 2weeks for 10years. Throughout the course of ERT, his leg ulcers recurred, and massive excretion of urinary globotriaosylceramide and plasma globotriaosylsphingosine was observed. Electron microscopy of the venous tissue in the regions of the ulcer showed massive typical zebra bodies in the vascular wall smooth muscle cells.

Pompe disease in Austria: clinical, genetic and epidemiological aspects

In this study, we performed a survey of infantile and late-onset Pompe disease (IOPD and LOPD) in Austria. Paediatric and neuromuscular centres were contacted to provide a set of anonymized clinical and genetic data of patients with IOPD and LOPD. The number of patients receiving enzyme replacement therapy (ERT) was obtained from the pharmaceutical company providing alglucosidase alfa. We found 25 patients in 24 families, 4 IOPD and 21 LOPD with a resulting prevalence of 1:350,914. The most frequent clinical manifestation in LOPD was a lower limb-girdle phenotype combined with axial weakness. Three patients were clinically pauci- or asymptomatic and were diagnosed because of persistent hyperCKemia. Diagnostic delay in LOPD was 7.4 ± 9.7 years. The most common mutation was c.-32-13T > G. All IOPD and 17 symptomatic LOPD patients are receiving ERT. Standardized follow-up was only available in six LOPD patients for the 6-min walk test (6minWT) and in ten for the forced vital capacity (FVC). Mean FVC did not decline (before ERT; 63.6 ± 39.7%; last evaluation during ERT: 61.9 ± 26.9%; P = 0.5) while there was a trend to decline in the mean distance covered by the 6minWT (before ERT: 373.5 ± 117.9 m; last evaluation during ERT: 308.5 ± 120.8 m; P = 0.077). The study shows a lower prevalence of Pompe disease in Austria than in other European countries and corroborates a limb-girdle phenotype with axial weakness as the most common clinical presentation, although asymptomatic hyperCKemia may be the first indication of LOPD.

The utility of the FIPI score in predicting long-term clinical outcomes in patients with Fabry disease receiving enzyme replacement therapy with agalsidase alfa.

Fabry disease is a rare X-linked lysosomal storage disorder in which there is deficiency of alpha galactosidase A. Enzyme replacement therapy (ERT) is commercially available and has been demonstrated to improve cardiac and renal outcomes. Predictive scores, such as the Fabry International Prognostic Index (FIPI), have been developed to stratify disease severity; however, these have not been validated to predict outcomes in patients receiving ERT. We show that the FIPI score at baseline can predict outcomes in a group of patients on long-term ERT.

Identification of Fabry Disease in a Tertiary Referral Cohort of Patients with Hypertrophic Cardiomyopathy

BackgroundFabry disease is an X-linked lysosomal storage disorder caused by the deficient activity of α-galactosidase A due to mutations in the GLA gene, which may be associated with increased left ventricular wall thickness and mimic the morphologic features of hypertrophic cardiomyopathy. Management strategies for these 2 diseases diverge, with Fabry disease–specific treatment utilizing recombinant α-galactosidase A enzyme replacement therapy. MethodsWe studied a prospectively assembled consecutive cohort of 585 patients (71% male) from 2 hypertrophic cardiomyopathy tertiary referral centers by screening for low α-galactosidase A activity in dried blood spots. Male patients with low α-galactosidase A activity levels and all females were tested for mutations in the GLA gene. ResultsIn 585 patients previously diagnosed with hypertrophic cardiomyopathy, we identified 2 unrelated patients (0.34%), both with the GLA mutation encoding P.N215S, the most common mutation causing later-onset Fabry disease phenotype. These patients were both asymptomatic, a man aged 53 years and a woman aged 69 years, and demonstrated a mild cardiac phenotype with symmetric distribution of left ventricular hypertrophy. After family screening, a total of 27 new Fabry disease patients aged 2-81 years were identified in the 2 families, including 12 individuals who are now receiving enzyme replacement therapy. ConclusionsThese observations support consideration for routine prospective screening for Fabry disease in all patients without a definitive etiology for left ventriclar hypertrophy. This strategy would likely result, through cascade family testing, in the earlier identification of new Fabry disease–affected males and female heterozygotes who may benefit from monitoring and/or enzyme replacement therapy.

AB073. Classic infantile-onset Pompe disease: phenotypes and outcomes of 5 Vietnamese patients receiving enzyme replacement therapy

Background: Pompe disease (PD) or glycogen storage disease type II is a lysosomal storage disorder, caused by mutations of GAA gene which results in deficiency of acid alpha-glucosidase (GAA) enzyme that involves in metabolism of glycogen in the lysosomes. Its incidence is 1/14,000–1/100,000. PD is divided into three types: classic infantile onset, non-classic infantile onset, and late onset. Early enzyme replacement therapy (ERT) before developing respiratory distress may lead to good outcome. Since 2013, we have identified 16 cases with classic infantile-onset and 5 cases were treated with ERT. Herein, we describe phenotypes and outcomes of five infantile-onset PD patients who received ERT.