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Elosulfase alfa decreases glycosaminoglycan storage in white blood cells from Morquio syndrome type A patients undergoing enzyme replacement
Abstracts / Molecular Genetics and Metabolism 114 (2015) S11–S130
CO
RR
EC
TE
DP
Neuronopathic Gaucher disease presents a clinical spectrum of neurological features from eye findings to seizures and in severe cases brain and central nervous system damage. Treatment via enzyme replacement therapy (ERT) is recommended, with excellent response for the visceral manifestations including bone health, but no impact on neurological disease. Recommendations suggest ERT doses upwards of 120 U/kg every two weeks for pediatric patients with neuropathic Gaucher and 60 U/kg every 2 weeks for adults (Altarescu et al., 2001; Vellodi et al., 2001). We report two patients with neuronopathic Gaucher (c.L444P homozygotes) maintained on high dose ERT who developed avascular necrosis (AVN) at 4.5 and 6 years post high dose ERT initiation, respectively. Patient 1 is a 13 year old Hispanic male who presented at age 14 months and began ERT at 60 U/kg every two weeks at age 17 months. ERT was increased to 120 U/kg every two weeks at age 2. He had normalization of visceral manifestations at the increased dose. At age 6.5 years, he presented with left-sided bone pain; X-rays revealed sclerosis, and flattening and widening of the left femoral epiphysis, consistent with AVN. At age 7 years, he presented with rightsided pain; X-rays revealed a femoral neck stress fracture, repaired by Spica cast. Bone density scan was within two standard deviations of the mean one month prior to the onset of pain. Biomarkers were previously stable; chitotriosidase level increased from 4511 to 8771 nmol/h/ml approximately one month before onset of pain. Patient 1 initiated weekly ERT dose of 60 U/kg after surgical repair and showed improvement. Routine MRI at age 13 noted worsening bilateral femoral head AVNs. Patient 2 is an 18 year old Caucasian male who presented at 18 months and began ERT at 22 months at a dose of 35 U/kg at an outside institution. He began care at Duke at age 4 years and continued on 35 U/kg. At 6.5 years, he was noted to have horizontal and vertical supranuclear gaze palsy, slow saccades, and difficulties with downward gaze. ERT dose was increased and maintained at 60 U/kg every 2 weeks; patient showed a good response, was growing and developing well without bone pain or symptoms. Routine surveillance MRI at age 17 noted a left femoral head AVN and bilateral femoral lytic lesions. Patient 2 was not reporting pain at this time. Previous surveillance MRI at age 15 was normal. We present 2 cases of c.L444P homozygotes developing bone crises and avascular necrosis in spite of optimum ERT dosing for neuropathic Gaucher. Registry data will be queried to identify any additional cases. Both cases demonstrate the need for regular surveillance imaging as AVNs can present in a short amount of time. These cases additionally exhibit current challenges in the ability to prevent manifestations in bone tissue of patients with Gaucher disease.
OF
Lauren A. Bailey, Jennifer Sullivan, Priya S. Kishnani, Duke University Medical Center, Durham, NC, USA
patient is a 16-year-old male diagnosed with Gaucher disease at 6 months. He presented with hepatosplenomegaly, hypoxemia (requiring hospitalization and oxygen supplementation), and ground glass infiltrates on lung CT. His neurological examination was and continues to be normal. Gaucher disease was confirmed based upon liver biopsy findings, deficient acid β-glucosidase activity in leukocytes and GBA1 mutations (L444P/A341T). His CYP2D6 genotype is *1/*2a (extensive metabolizer). However some laboratories conclude that these alleles are more consistent with an ultra-rapid metabolizer state. In addition to Gaucher disease the patient has been diagnosed with hereditary spherocytosis and an inherited thrombophilia. Imiglucerase therapy was initiated at approximately 6 months of age. He received uninterrupted infusions at a dose of 40–60 units/kg either weekly or every two weeks until 2009 (age 12). In 2010, he switched to velaglucerase alfa (similar dose) due to an inadequate imiglucerase supply. In 2012 the velaglucerase alfa dose was increased to 60 units/kg weekly in an effort to optimize his response to enzyme therapy. At the time that the velaglucerase alfa/eliglustat therapeutic protocol was initiated the patient had a normal sized liver, mildly enlarged spleen, normal hematologic profile, and mildly elevated LFTs. He had a history of bilateral avascular necrosis of the hips, pulmonary embolism with secondary pulmonary hypertension, and several aortic emboli. His primary clinical complaint was shortness of breath at rest and with exertion despite resolution of pulmonary emboli and pulmonary hypertension. His chest and abdominal CT showed densely calcified central lymph nodes and an infiltrative process consistent with Gaucher disease. He was unable to walk his dog one block, had many school absences due to fatigue and illness, and could not walk to classes without using an elevator or taking breaks. He reported his quality of life to be a 1/10. After one year on the combination protocol all measures of Gaucher disease have remained stable with no reports of bone pain or crises and no back pain. Repeat lavage revealed a significant decrease in storage macrophages, although no measurable differences could be observed on chest X-ray, PFTs, or chest CT. Currently, he easily gets through the school day without fatigue and walks to all classes without shortness of breath. He snowboarded in the Rockies at N10,000 ft in the winter and wake-boarded and water skied over the summer. He carried a full set of golf clubs when walking a 9-hole golf course. He went on a two-week mission trip and performed manual labor without any trouble. He currently reports his quality of life to be an 8/10. There were no serious adverse events reported. In conclusion, this patient has done well on combination velaglucerase alfa and eliglustat with significant improvement in stamina and endurance and no significant safety issues identified.
RO
17 Avascular necrosis in neuronopathic Gaucher despite high-dose enzyme replacement therapy
S17
UN
doi:10.1016/j.ymgme.2014.12.019
18 Combination therapy (eliglustat + velaglucerase alfa) in a pediatric patient with Gaucher disease type 1 and hereditary spherocytosis Laurie Baileya, Daniel Ambrusob, Gregory Grabowskia, Thomas A. Burrowa, aCincinnati Children's Hospital, Cincinnati, OH, USA, bColorado Children's Hospital, Denver, CO, USA We report the results of a pediatric patient with Gaucher disease type 1, hereditary spherocytosis, and thrombophila treated for one year with combination enzyme replacement therapy (velaglucerase alfa 60 units/kg weekly) and eliglustat (84 mg twice daily). The
doi:10.1016/j.ymgme.2014.12.020
19 Elosulfase alfa decreases glycosaminoglycan storage in white blood cells from Morquio syndrome type A patients undergoing enzyme replacement Guilherme Baldo, Fabiano Poswar, Andressa Federhen, Rejane Gus, Fernanda Bender, Roberto Giugliani, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil Mucopolysaccharidosis IVA (MPS IVA; Morquio syndrome type A) is a lysosomal disorder caused by a deficiency of N-acetylgalactosamine6-sulfate sulfatase (GALNS) activity, leading to cellular storage of keratan sulfate (KS). Recently, enzyme replacement therapy (ERT) was approved for MPS IVA (Vimizim, BioMarin Pharmaceutical). Initial studies demonstrated that the drug is safe, improves the 6-min walk test results and leads to normalization of urinary KS levels. Although
Abstracts / Molecular Genetics and Metabolism 114 (2015) S11–S130
OF
month later he had pneumonia that resolved with ampicillin; twentyfive days after this, ERT with Imiglucerase began with 120 U/kg. This same day it was painful to mobilize the limb and the left hip which was normal by Rx. Diagnosed as a BC, he began with tramadol and paracetamol; 3 days later, he had increased thigh volume, pain and functional disability. USG hip Dx of septic arthritis by USG, NMR: femur bone infarction likely bone crises vs osteomyelitis. Presents with: fever: 38.2 °C, Hb: 8.1, WBC: 8800, 16% neutrophils, 60% lymphocytes, platelets: 83,000, ESR: 21 mm, CRP: 6.35; starting treatment with cefotaxime, dicloxacillin, immobilization. ACT LOWER LIMB: compatible with osteomyelitis, but indistinguishable from bone crisis. NMR LOWER LIMB: osteomyelitis in left femur, accompanied by subperiosteal abscess, Brodie's abscess. Scintigram UBI showed an infectious process in resolution that increased uptake in soft tissues of the distal femur. Hg 10.4, 5200 leukocytes 27% neutrophils, 63% lymphocytes, 115,000 platelets, bone biopsy: chronic osteomyelitis, negative culture; 2nd infusion of Imiglucerase decreased splenomegaly, and there was platelet count improvement. TC99 scintigraphy showed increased osteogenic activity. May 22: fever 38.2 °C, poor outcome, BH: 10.4, leukocyte: 4100, platelet: 137,000, and ESR: 19 mm. Cefotaxime/Vancomycin and Tramadol. 2nd biopsy: osteomyelitis, w/negative culture. Cefotaxime 7 weeks, Vancomycin 2 weeks, good clinical outcome, retirement immobilization. June 6: 14 Hb: 10.6, leukocytes: 4500, platelets: 108,000, ESR: 2 mm. Hospital discharge. A history of serious infection (pneumonia) with development of bone pain and functional disability gave suspicions of acute osteomyelitis and antimicrobial management was started as described. However, the radiological findings are indistinguishable from a Gaucher's BC, unexpected in such a young patient. The clinical course and radiological evolution support the diagnosis of acute osteomyelitis. The clinical and radiological bone crisis of Gaucher disease may be indistinguishable from acute osteomyelitis, but in this history of serious infection it was determinative of antimicrobial treatment; this situation may be common in patients with Gaucher disease and complicates the differential diagnosis.
TE
DP
promising, there is still a lack of knowledge about the spectrum of effects of ERT on MPS IVA manifestations. GAG storage occurs in multiple organs, including bone marrow, heart muscle, and visceral organs and these abnormalities can cause significant morbidity and lead to death. Therefore, the goal of this study was to evaluate the effects of 6 months of ERT upon GAG storage in peripheral blood white blood cells (WBCs) of MPS IVA patients who participated in a phase III doubleblind placebo-controlled randomized clinical trial (Strive, sponsored by BioMarin Pharmaceutical), comparing samples from three different patient groups: patients that received weekly infusions (2 mg/kg) of enzyme (ERT-W, n = 6) versus patients who received infusions every other week (ERT-EOW, n = 6) versus patients enrolled in the placebo (PLA, n = 4) group. Peripheral blood was collected, and blood smears were stained with May–Grunwald–Giemsa. One hundred WBCs were evaluated for GAG granules, and cells were classified as (1) cells with no visible GAG granules; or (2) cells containing between 1 and 10 granules; or (3) cells with more than 10 granules in the cytoplasm. Statistical analysis was performed using SPSS with Tukey test as post hoc cells from placebo-treated patients presented several granules on the cytoplasm, which were reduced in the cells from ERT-treated patients. Comparing placebo versus both treated groups together, ERT increased the number of cells without observed GAG storage (18.0 ± 8.1% of cells with no storage observed in placebo vs 48.5 ± 22.5% in ERT treated, P b 0.01) and reduced the number of cells with more than 10 granules in the cytoplasm (21.3 ± 7.3% in placebo vs 8.3 ± 5.2% in ERT, P b 0.01) suggesting that ERT was effective in reducing GAG storage. When the treated groups were separated according to regimen, ERT-W patients had the biggest improvement (58.3% of cells with no storage, P = 0.012 vs placebo), while ERT-EOW had intermediate levels of cells with no GAG (51.2%, P = 0.058 vs placebo). Also, cells presenting more than 10 granules were reduced in both treated groups (21.3 ± 7.3% in placebo vs 9.5 ± 3.3% in ERT-EOW and only 5.0 ± 6.7% in ERT-W, P b 0.01 in both cases). Our results suggest that treatment with ERT decreases WBC GAG storage, which is an indicator that the visceral features of the disease are approached by this therapy. Weekly ERT (as approved by the FDA) showed slightly better performance than ERT-EOW. Whether this cellular improvement could be translated to clinical benefits is something still to be evaluated.
RO
S18
EC
RR
doi:10.1016/j.ymgme.2014.12.021
20 Osteomyelitis in a breastfed child with Gaucher disease type I with an indistinguishable bone crisis
CO
Edgar Barajas, Magdalena Ceron, Hospital Infantil de Mèxico Federico Gòmez, Mexico, Mexico Gaucher disease LSD is characterized by hepatosplenomegaly, anemia, thrombocytopenia, bone pain crises and pathological fractures that present as the disease progresses, although this last one is not usual in young children. Acute osteomyelitis may be a complication in patients with Gaucher disease that is clinically and radiologically indistinguishable. Patient was male, 1.4 years of age of not consanguineous parents, GIII, with 2 healthy siblings, born by preterm delivery 34 weeks of gestation, and recovered with mild asphyxia; full immunization scheme. At 6 months of age his mother notes increased abdominal volume, detention of growth, and recurrent respiratory tract infections. At 1 year of age, he presented with 2 community-acquired pneumonias and massive hepatosplenomegaly, anemia and thrombocytopenia, epistaxis, petechiae scattered; malnutrition GII; bone marrow aspirate: Gaucher cells. USG showed massive hepato-splenomegaly: spleen 11 cm, vol. 312 cm3, liver 13 cm. β-Glucocerebrosidase enzyme activity is 0.78 (N3.61), positive molecular study: mutation homozygous of c1448TNC. A
UN
doi:10.1016/j.ymgme.2014.12.022
21 Fabry disease in untreated women with enzyme replacement therapy: Symptomatology and clinical profile
Miguel A. Barba-Romeroa, Vicente Climentb, Víctor Valverdec, Joaquín Serenad, Rafael Huertase, Jose A. Herrerof, Josep M. Puigg, Roser Torrah, aHospital Universitario de Albacete, Albacete, Spain, bHospital Universitario de Alicante, Alicante, Spain, cHospital Universitario de Elda, Alicante, Spain, dHospital Josep Trueta de Girona, Girona, Spain, e Hospital La Mancha Centro, Ciudad Real, Spain, fHospital Clínico San Carlos, Madrid, Spain, gHospital del Mar, Barcelona, Spain, hFundación Puigvert, Barcelona, Spain The purpose of this study was the assessment of the health status of women diagnosed with Fabry disease (FD) who do not receive Enzyme Replacement Therapy (ERT) from a population not included in the Fabry Outcome Survey (FOS) registry. It was a cross-sectional, observational, multicentre study in four Autonomous Communities of Spain. Patients, who attended their clinics as part of their routine follow-up and signed an informed consent, completed a questionnaire including the Brief Pain Inventory, Euroqol-5D and Neurological Severity Score. Mainz Severity Score Index and Fabry International Prognosis Index were calculated. Clinical data, blood and urine tests, as well as clinical assessments (e.g. echocardiography) for the previous year were collected by their clinicians retrospectively from their clinical records (CR). A total of 33 women, mean age 45.6 (SD 16.2) years old, were recruited in seven centres.
CO
RR
EC
TE
DP
Neuronopathic Gaucher disease presents a clinical spectrum of neurological features from eye findings to seizures and in severe cases brain and central nervous system damage. Treatment via enzyme replacement therapy (ERT) is recommended, with excellent response for the visceral manifestations including bone health, but no impact on neurological disease. Recommendations suggest ERT doses upwards of 120 U/kg every two weeks for pediatric patients with neuropathic Gaucher and 60 U/kg every 2 weeks for adults (Altarescu et al., 2001; Vellodi et al., 2001). We report two patients with neuronopathic Gaucher (c.L444P homozygotes) maintained on high dose ERT who developed avascular necrosis (AVN) at 4.5 and 6 years post high dose ERT initiation, respectively. Patient 1 is a 13 year old Hispanic male who presented at age 14 months and began ERT at 60 U/kg every two weeks at age 17 months. ERT was increased to 120 U/kg every two weeks at age 2. He had normalization of visceral manifestations at the increased dose. At age 6.5 years, he presented with left-sided bone pain; X-rays revealed sclerosis, and flattening and widening of the left femoral epiphysis, consistent with AVN. At age 7 years, he presented with rightsided pain; X-rays revealed a femoral neck stress fracture, repaired by Spica cast. Bone density scan was within two standard deviations of the mean one month prior to the onset of pain. Biomarkers were previously stable; chitotriosidase level increased from 4511 to 8771 nmol/h/ml approximately one month before onset of pain. Patient 1 initiated weekly ERT dose of 60 U/kg after surgical repair and showed improvement. Routine MRI at age 13 noted worsening bilateral femoral head AVNs. Patient 2 is an 18 year old Caucasian male who presented at 18 months and began ERT at 22 months at a dose of 35 U/kg at an outside institution. He began care at Duke at age 4 years and continued on 35 U/kg. At 6.5 years, he was noted to have horizontal and vertical supranuclear gaze palsy, slow saccades, and difficulties with downward gaze. ERT dose was increased and maintained at 60 U/kg every 2 weeks; patient showed a good response, was growing and developing well without bone pain or symptoms. Routine surveillance MRI at age 17 noted a left femoral head AVN and bilateral femoral lytic lesions. Patient 2 was not reporting pain at this time. Previous surveillance MRI at age 15 was normal. We present 2 cases of c.L444P homozygotes developing bone crises and avascular necrosis in spite of optimum ERT dosing for neuropathic Gaucher. Registry data will be queried to identify any additional cases. Both cases demonstrate the need for regular surveillance imaging as AVNs can present in a short amount of time. These cases additionally exhibit current challenges in the ability to prevent manifestations in bone tissue of patients with Gaucher disease.
OF
Lauren A. Bailey, Jennifer Sullivan, Priya S. Kishnani, Duke University Medical Center, Durham, NC, USA
patient is a 16-year-old male diagnosed with Gaucher disease at 6 months. He presented with hepatosplenomegaly, hypoxemia (requiring hospitalization and oxygen supplementation), and ground glass infiltrates on lung CT. His neurological examination was and continues to be normal. Gaucher disease was confirmed based upon liver biopsy findings, deficient acid β-glucosidase activity in leukocytes and GBA1 mutations (L444P/A341T). His CYP2D6 genotype is *1/*2a (extensive metabolizer). However some laboratories conclude that these alleles are more consistent with an ultra-rapid metabolizer state. In addition to Gaucher disease the patient has been diagnosed with hereditary spherocytosis and an inherited thrombophilia. Imiglucerase therapy was initiated at approximately 6 months of age. He received uninterrupted infusions at a dose of 40–60 units/kg either weekly or every two weeks until 2009 (age 12). In 2010, he switched to velaglucerase alfa (similar dose) due to an inadequate imiglucerase supply. In 2012 the velaglucerase alfa dose was increased to 60 units/kg weekly in an effort to optimize his response to enzyme therapy. At the time that the velaglucerase alfa/eliglustat therapeutic protocol was initiated the patient had a normal sized liver, mildly enlarged spleen, normal hematologic profile, and mildly elevated LFTs. He had a history of bilateral avascular necrosis of the hips, pulmonary embolism with secondary pulmonary hypertension, and several aortic emboli. His primary clinical complaint was shortness of breath at rest and with exertion despite resolution of pulmonary emboli and pulmonary hypertension. His chest and abdominal CT showed densely calcified central lymph nodes and an infiltrative process consistent with Gaucher disease. He was unable to walk his dog one block, had many school absences due to fatigue and illness, and could not walk to classes without using an elevator or taking breaks. He reported his quality of life to be a 1/10. After one year on the combination protocol all measures of Gaucher disease have remained stable with no reports of bone pain or crises and no back pain. Repeat lavage revealed a significant decrease in storage macrophages, although no measurable differences could be observed on chest X-ray, PFTs, or chest CT. Currently, he easily gets through the school day without fatigue and walks to all classes without shortness of breath. He snowboarded in the Rockies at N10,000 ft in the winter and wake-boarded and water skied over the summer. He carried a full set of golf clubs when walking a 9-hole golf course. He went on a two-week mission trip and performed manual labor without any trouble. He currently reports his quality of life to be an 8/10. There were no serious adverse events reported. In conclusion, this patient has done well on combination velaglucerase alfa and eliglustat with significant improvement in stamina and endurance and no significant safety issues identified.
RO
17 Avascular necrosis in neuronopathic Gaucher despite high-dose enzyme replacement therapy
S17
UN
doi:10.1016/j.ymgme.2014.12.019
18 Combination therapy (eliglustat + velaglucerase alfa) in a pediatric patient with Gaucher disease type 1 and hereditary spherocytosis Laurie Baileya, Daniel Ambrusob, Gregory Grabowskia, Thomas A. Burrowa, aCincinnati Children's Hospital, Cincinnati, OH, USA, bColorado Children's Hospital, Denver, CO, USA We report the results of a pediatric patient with Gaucher disease type 1, hereditary spherocytosis, and thrombophila treated for one year with combination enzyme replacement therapy (velaglucerase alfa 60 units/kg weekly) and eliglustat (84 mg twice daily). The
doi:10.1016/j.ymgme.2014.12.020
19 Elosulfase alfa decreases glycosaminoglycan storage in white blood cells from Morquio syndrome type A patients undergoing enzyme replacement Guilherme Baldo, Fabiano Poswar, Andressa Federhen, Rejane Gus, Fernanda Bender, Roberto Giugliani, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil Mucopolysaccharidosis IVA (MPS IVA; Morquio syndrome type A) is a lysosomal disorder caused by a deficiency of N-acetylgalactosamine6-sulfate sulfatase (GALNS) activity, leading to cellular storage of keratan sulfate (KS). Recently, enzyme replacement therapy (ERT) was approved for MPS IVA (Vimizim, BioMarin Pharmaceutical). Initial studies demonstrated that the drug is safe, improves the 6-min walk test results and leads to normalization of urinary KS levels. Although
Abstracts / Molecular Genetics and Metabolism 114 (2015) S11–S130
OF
month later he had pneumonia that resolved with ampicillin; twentyfive days after this, ERT with Imiglucerase began with 120 U/kg. This same day it was painful to mobilize the limb and the left hip which was normal by Rx. Diagnosed as a BC, he began with tramadol and paracetamol; 3 days later, he had increased thigh volume, pain and functional disability. USG hip Dx of septic arthritis by USG, NMR: femur bone infarction likely bone crises vs osteomyelitis. Presents with: fever: 38.2 °C, Hb: 8.1, WBC: 8800, 16% neutrophils, 60% lymphocytes, platelets: 83,000, ESR: 21 mm, CRP: 6.35; starting treatment with cefotaxime, dicloxacillin, immobilization. ACT LOWER LIMB: compatible with osteomyelitis, but indistinguishable from bone crisis. NMR LOWER LIMB: osteomyelitis in left femur, accompanied by subperiosteal abscess, Brodie's abscess. Scintigram UBI showed an infectious process in resolution that increased uptake in soft tissues of the distal femur. Hg 10.4, 5200 leukocytes 27% neutrophils, 63% lymphocytes, 115,000 platelets, bone biopsy: chronic osteomyelitis, negative culture; 2nd infusion of Imiglucerase decreased splenomegaly, and there was platelet count improvement. TC99 scintigraphy showed increased osteogenic activity. May 22: fever 38.2 °C, poor outcome, BH: 10.4, leukocyte: 4100, platelet: 137,000, and ESR: 19 mm. Cefotaxime/Vancomycin and Tramadol. 2nd biopsy: osteomyelitis, w/negative culture. Cefotaxime 7 weeks, Vancomycin 2 weeks, good clinical outcome, retirement immobilization. June 6: 14 Hb: 10.6, leukocytes: 4500, platelets: 108,000, ESR: 2 mm. Hospital discharge. A history of serious infection (pneumonia) with development of bone pain and functional disability gave suspicions of acute osteomyelitis and antimicrobial management was started as described. However, the radiological findings are indistinguishable from a Gaucher's BC, unexpected in such a young patient. The clinical course and radiological evolution support the diagnosis of acute osteomyelitis. The clinical and radiological bone crisis of Gaucher disease may be indistinguishable from acute osteomyelitis, but in this history of serious infection it was determinative of antimicrobial treatment; this situation may be common in patients with Gaucher disease and complicates the differential diagnosis.
TE
DP
promising, there is still a lack of knowledge about the spectrum of effects of ERT on MPS IVA manifestations. GAG storage occurs in multiple organs, including bone marrow, heart muscle, and visceral organs and these abnormalities can cause significant morbidity and lead to death. Therefore, the goal of this study was to evaluate the effects of 6 months of ERT upon GAG storage in peripheral blood white blood cells (WBCs) of MPS IVA patients who participated in a phase III doubleblind placebo-controlled randomized clinical trial (Strive, sponsored by BioMarin Pharmaceutical), comparing samples from three different patient groups: patients that received weekly infusions (2 mg/kg) of enzyme (ERT-W, n = 6) versus patients who received infusions every other week (ERT-EOW, n = 6) versus patients enrolled in the placebo (PLA, n = 4) group. Peripheral blood was collected, and blood smears were stained with May–Grunwald–Giemsa. One hundred WBCs were evaluated for GAG granules, and cells were classified as (1) cells with no visible GAG granules; or (2) cells containing between 1 and 10 granules; or (3) cells with more than 10 granules in the cytoplasm. Statistical analysis was performed using SPSS with Tukey test as post hoc cells from placebo-treated patients presented several granules on the cytoplasm, which were reduced in the cells from ERT-treated patients. Comparing placebo versus both treated groups together, ERT increased the number of cells without observed GAG storage (18.0 ± 8.1% of cells with no storage observed in placebo vs 48.5 ± 22.5% in ERT treated, P b 0.01) and reduced the number of cells with more than 10 granules in the cytoplasm (21.3 ± 7.3% in placebo vs 8.3 ± 5.2% in ERT, P b 0.01) suggesting that ERT was effective in reducing GAG storage. When the treated groups were separated according to regimen, ERT-W patients had the biggest improvement (58.3% of cells with no storage, P = 0.012 vs placebo), while ERT-EOW had intermediate levels of cells with no GAG (51.2%, P = 0.058 vs placebo). Also, cells presenting more than 10 granules were reduced in both treated groups (21.3 ± 7.3% in placebo vs 9.5 ± 3.3% in ERT-EOW and only 5.0 ± 6.7% in ERT-W, P b 0.01 in both cases). Our results suggest that treatment with ERT decreases WBC GAG storage, which is an indicator that the visceral features of the disease are approached by this therapy. Weekly ERT (as approved by the FDA) showed slightly better performance than ERT-EOW. Whether this cellular improvement could be translated to clinical benefits is something still to be evaluated.
RO
S18
EC
RR
doi:10.1016/j.ymgme.2014.12.021
20 Osteomyelitis in a breastfed child with Gaucher disease type I with an indistinguishable bone crisis
CO
Edgar Barajas, Magdalena Ceron, Hospital Infantil de Mèxico Federico Gòmez, Mexico, Mexico Gaucher disease LSD is characterized by hepatosplenomegaly, anemia, thrombocytopenia, bone pain crises and pathological fractures that present as the disease progresses, although this last one is not usual in young children. Acute osteomyelitis may be a complication in patients with Gaucher disease that is clinically and radiologically indistinguishable. Patient was male, 1.4 years of age of not consanguineous parents, GIII, with 2 healthy siblings, born by preterm delivery 34 weeks of gestation, and recovered with mild asphyxia; full immunization scheme. At 6 months of age his mother notes increased abdominal volume, detention of growth, and recurrent respiratory tract infections. At 1 year of age, he presented with 2 community-acquired pneumonias and massive hepatosplenomegaly, anemia and thrombocytopenia, epistaxis, petechiae scattered; malnutrition GII; bone marrow aspirate: Gaucher cells. USG showed massive hepato-splenomegaly: spleen 11 cm, vol. 312 cm3, liver 13 cm. β-Glucocerebrosidase enzyme activity is 0.78 (N3.61), positive molecular study: mutation homozygous of c1448TNC. A
UN
doi:10.1016/j.ymgme.2014.12.022
21 Fabry disease in untreated women with enzyme replacement therapy: Symptomatology and clinical profile
Miguel A. Barba-Romeroa, Vicente Climentb, Víctor Valverdec, Joaquín Serenad, Rafael Huertase, Jose A. Herrerof, Josep M. Puigg, Roser Torrah, aHospital Universitario de Albacete, Albacete, Spain, bHospital Universitario de Alicante, Alicante, Spain, cHospital Universitario de Elda, Alicante, Spain, dHospital Josep Trueta de Girona, Girona, Spain, e Hospital La Mancha Centro, Ciudad Real, Spain, fHospital Clínico San Carlos, Madrid, Spain, gHospital del Mar, Barcelona, Spain, hFundación Puigvert, Barcelona, Spain The purpose of this study was the assessment of the health status of women diagnosed with Fabry disease (FD) who do not receive Enzyme Replacement Therapy (ERT) from a population not included in the Fabry Outcome Survey (FOS) registry. It was a cross-sectional, observational, multicentre study in four Autonomous Communities of Spain. Patients, who attended their clinics as part of their routine follow-up and signed an informed consent, completed a questionnaire including the Brief Pain Inventory, Euroqol-5D and Neurological Severity Score. Mainz Severity Score Index and Fabry International Prognosis Index were calculated. Clinical data, blood and urine tests, as well as clinical assessments (e.g. echocardiography) for the previous year were collected by their clinicians retrospectively from their clinical records (CR). A total of 33 women, mean age 45.6 (SD 16.2) years old, were recruited in seven centres.