- Email: [email protected]
Fabry disease in untreated women with enzyme replacement therapy: Symptomatology and clinical profile
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.
Abstracts / Molecular Genetics and Metabolism 114 (2015) S11–S130
RO
OF
and compared with findings from age and leg length matched controls. Data generated from the GaitRite indicated that gait pattern is different in Hunter disease patients compared to controls. MPS II patients showed lower velocity, shorter step length and wider base of support. Two out of six patients showed signs of improvement in velocity after the initiation of ERT but eventually 5/6 patients dropped below the 3rd centile during the course of the disease. Step length was evidently affected in patients with Hunter disease at baseline before the administration of ERT. Two patients improved but all participants dropped below the 3rd centile during the followup period. Finally, observations of base of support varied throughout the assessment period but no clear pattern emerged and there was great fluctuation in the findings. The small number of patients limited any comparison between neurologically and non-neurologically affected patients. Using the GaitRite system we have been able to identify alterations in various gait parameters in a small group of patients with MPS II. Our findings need to be reconfirmed in studies with a larger population of patients. However, even with the limited number of patients our results indicate that GaitRite could represent a useful tool for the assessment of functional mobility in Hunter syndrome and for tracking the effect over time of ERT. doi:10.1016/j.ymgme.2014.12.024
23 Long-term effectiveness of agalsidase alfa enzyme replacement in Fabry disease: A Fabry Outcome Survey analysis
DP
The median age at symptom onset was 35.5 years old [IQR: 30.0– 51.5], being 42.0 years old [IQR: 30.0–54.0] at diagnosis (median time to diagnosis 2 years (IQR: 1.0–5.0)). Only one patient was an index case. The self-referred disease status was mild, with 69% referring themselves as asymptomatic and 63.2% defining their life as normal, whereas clinicians considered them only 33.3% as asymptomatic. Twenty-two patients showed, at least, one symptom related to FD (66.7%). The most frequent symptoms were: tickling at the hands and feet (40:9%) and palpitation, constipation, joint pain, headache, dizziness and hypohidrosis (27.3%). The clinical records had incomplete urine test data for 33 to 57.6% patients, and only about 50% did have post-diagnostic cardiovascular tests. Blood tests showed altered levels of haematocrit (b42%), haemoglobin (b13.5 g/L) and iron (b60 mcg/dL) for 76.0%, 56.0% and 72.2% patients respectively and 38.5% showed hypercholesterolemia (cholesterol N 5.17 mmol/L). Despite symptom information and clinician's opinion, the ERT was not offered to 96.4% of women and 62.5% of patients did not receive any other symptomatic treatment. Three different types of mutations were found: deletion (n = 9, 28.1%); Missense (n = 22, 68.8%); Nonsense (n = 1, 3.1%). Patients harbouring a deletion compared with those with a missense mutation had higher NSS scores for the autonomic symptoms [2.0 (0.0–3.0) vs. 0.0 (0.0–0.0); p = 0.012] and for the total punctuation [3.0 (0.0–5.0) vs. 0.0 (0.0–1.0); p = 0.023], although the level of affectation was mild. As a conclusion, heterozygous FD women who do not receive ERT showed symptoms of FD, had incomplete follow-up records and, in this sample, had not received other symptomatic treatment. Despite two thirds of women who suffered from mild typical symptoms of FD, they were not offered ERT or other symptomatic treatment apparently. This situation may be critical for patients harbouring deletions, who seemingly may be more symptomatic.
Michael Becka, Derralynn Hughesb, Christoph Kampmanna, Sylvain Larroquec, Atul Mehtab, Guillem Pintos-Morelld, Uma Ramaswamib, Michael Weste, Anna Wijatykf, Roberto Giuglianig, aUniversity Medical Center, University of Mainz, Department of Paediatrics, Mainz, Germany, b Royal Free London NHS Foundation Trust, University College of London, London, UK, cShire, Zug, Switzerland, dDepartment of Pediatrics, University Hospital “Germans Trias i Pujol”, Universitat Autònoma de Barcelona, Badalona, Spain, eDepartment of Medicine, Dalhousie University, Halifax, NS, Canada, fShire, Lexington, MA, USA, gMedical Genetics Service HCPA/Dep Genet UFRGS, INAGEMP, Porto Alegre, Brazil
TE
doi:10.1016/j.ymgme.2014.12.023
EC
22 Alterations in gait pattern in Hunter disease patients undergoing enzyme replacement therapy as assessed by the GaitRite system: A six year follow up
RR
Spyros Batzios, Michelle Wood, Lara Abulhoul, Maureen Cleary, Ashok Vellodi, Great Ormond Street Hospital, London, UK
CO
MPS II (Hunter syndrome) results from deficiency in the enzyme iduronate-2-sulfatase. Affected patients suffer from a wide spectrum of progressive multi-systemic manifestations. Limitations in functional mobility represent a common feature among the majority of patients, usually resulting from skeletal involvement and progressive arthropathy which occur early in the course of the disease. Enzyme replacement therapy (ERT) is available for this condition and has shown to improve several aspects of the disease. The introduction of ERT demands robust assessment tools for the monitoring of efficacy over time. Such tools are limited. We have previously highlighted the utility of the GaitRite system in MPS II where we showed abnormalities in gait. In this follow-up study we report the change in gait after 6 years of ERT. Six patients (three with neurological involvement) with MPS II formed the study group. The assessment of patients was performed using the GaitRite system, an electronic pressure sensitive walkway system which can identify changes in gait pattern through the course of the disease. Patients have been assessed at baseline and sequentially following the administration of ERT. Each boy walked at preferred speed and data was collected from 4 consecutive passes on the GaitRite mat. Individual characteristics of gait, such as velocity, step length and base of support have been assessed. Alterations in the studied parameters have been analysed
UN
S19
Outcomes from 5 years of treatment with agalsidase alfa enzyme replacement therapy (ERT) for Fabry disease in patients enrolled in the Fabry Outcomes Survey (FOS) were compared with published findings for untreated patients with Fabry disease.1,2,3 Data were extracted from FOS, a Shire-sponsored database, for comparison with data from three published studies. Outcomes evaluated were annualized for rate of change in estimated glomerular filtration rate (eGFR) and left ventricular mass indexed to height (LVMI) as well as time to and ages at a composite morbidity endpoint and at death. FOS data were extracted for 740 treated patients who were followed for a median of approximately 5 years. Compared with no treatment, patients treated with agalsidase alfa demonstrated slower decline in renal function and slower progression of left ventricular hypertrophy. Male treated patients with baseline eGFR b60 mL/min/1.73 m2 had a mean (standard error of the mean [SEM]) annualized change in eGFR of − 2.86 (0.53) mL/min/1.73 m2/y compared with −6.8 (1.5) in the published untreated cohort. The mean (SEM) rate of LVMI increase with treatment was 0.33 (0.10) g/m2.7/y in males and 0.48 (0.09) in females, compared with 4.07 (1.03) in untreated males and 2.31 (0.81) in untreated females. Morbidity occurred later in treated patients, with ~ 15% risk after 24 months with ERT versus ~45% risk without treatment, with first events and deaths also occurring at older ages in patients administered ERT (e.g., estimated 50% risk at 77.5 years versus 60 years in males). Findings from these retrospective comparisons of observational data and published literature
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.
Abstracts / Molecular Genetics and Metabolism 114 (2015) S11–S130
RO
OF
and compared with findings from age and leg length matched controls. Data generated from the GaitRite indicated that gait pattern is different in Hunter disease patients compared to controls. MPS II patients showed lower velocity, shorter step length and wider base of support. Two out of six patients showed signs of improvement in velocity after the initiation of ERT but eventually 5/6 patients dropped below the 3rd centile during the course of the disease. Step length was evidently affected in patients with Hunter disease at baseline before the administration of ERT. Two patients improved but all participants dropped below the 3rd centile during the followup period. Finally, observations of base of support varied throughout the assessment period but no clear pattern emerged and there was great fluctuation in the findings. The small number of patients limited any comparison between neurologically and non-neurologically affected patients. Using the GaitRite system we have been able to identify alterations in various gait parameters in a small group of patients with MPS II. Our findings need to be reconfirmed in studies with a larger population of patients. However, even with the limited number of patients our results indicate that GaitRite could represent a useful tool for the assessment of functional mobility in Hunter syndrome and for tracking the effect over time of ERT. doi:10.1016/j.ymgme.2014.12.024
23 Long-term effectiveness of agalsidase alfa enzyme replacement in Fabry disease: A Fabry Outcome Survey analysis
DP
The median age at symptom onset was 35.5 years old [IQR: 30.0– 51.5], being 42.0 years old [IQR: 30.0–54.0] at diagnosis (median time to diagnosis 2 years (IQR: 1.0–5.0)). Only one patient was an index case. The self-referred disease status was mild, with 69% referring themselves as asymptomatic and 63.2% defining their life as normal, whereas clinicians considered them only 33.3% as asymptomatic. Twenty-two patients showed, at least, one symptom related to FD (66.7%). The most frequent symptoms were: tickling at the hands and feet (40:9%) and palpitation, constipation, joint pain, headache, dizziness and hypohidrosis (27.3%). The clinical records had incomplete urine test data for 33 to 57.6% patients, and only about 50% did have post-diagnostic cardiovascular tests. Blood tests showed altered levels of haematocrit (b42%), haemoglobin (b13.5 g/L) and iron (b60 mcg/dL) for 76.0%, 56.0% and 72.2% patients respectively and 38.5% showed hypercholesterolemia (cholesterol N 5.17 mmol/L). Despite symptom information and clinician's opinion, the ERT was not offered to 96.4% of women and 62.5% of patients did not receive any other symptomatic treatment. Three different types of mutations were found: deletion (n = 9, 28.1%); Missense (n = 22, 68.8%); Nonsense (n = 1, 3.1%). Patients harbouring a deletion compared with those with a missense mutation had higher NSS scores for the autonomic symptoms [2.0 (0.0–3.0) vs. 0.0 (0.0–0.0); p = 0.012] and for the total punctuation [3.0 (0.0–5.0) vs. 0.0 (0.0–1.0); p = 0.023], although the level of affectation was mild. As a conclusion, heterozygous FD women who do not receive ERT showed symptoms of FD, had incomplete follow-up records and, in this sample, had not received other symptomatic treatment. Despite two thirds of women who suffered from mild typical symptoms of FD, they were not offered ERT or other symptomatic treatment apparently. This situation may be critical for patients harbouring deletions, who seemingly may be more symptomatic.
Michael Becka, Derralynn Hughesb, Christoph Kampmanna, Sylvain Larroquec, Atul Mehtab, Guillem Pintos-Morelld, Uma Ramaswamib, Michael Weste, Anna Wijatykf, Roberto Giuglianig, aUniversity Medical Center, University of Mainz, Department of Paediatrics, Mainz, Germany, b Royal Free London NHS Foundation Trust, University College of London, London, UK, cShire, Zug, Switzerland, dDepartment of Pediatrics, University Hospital “Germans Trias i Pujol”, Universitat Autònoma de Barcelona, Badalona, Spain, eDepartment of Medicine, Dalhousie University, Halifax, NS, Canada, fShire, Lexington, MA, USA, gMedical Genetics Service HCPA/Dep Genet UFRGS, INAGEMP, Porto Alegre, Brazil
TE
doi:10.1016/j.ymgme.2014.12.023
EC
22 Alterations in gait pattern in Hunter disease patients undergoing enzyme replacement therapy as assessed by the GaitRite system: A six year follow up
RR
Spyros Batzios, Michelle Wood, Lara Abulhoul, Maureen Cleary, Ashok Vellodi, Great Ormond Street Hospital, London, UK
CO
MPS II (Hunter syndrome) results from deficiency in the enzyme iduronate-2-sulfatase. Affected patients suffer from a wide spectrum of progressive multi-systemic manifestations. Limitations in functional mobility represent a common feature among the majority of patients, usually resulting from skeletal involvement and progressive arthropathy which occur early in the course of the disease. Enzyme replacement therapy (ERT) is available for this condition and has shown to improve several aspects of the disease. The introduction of ERT demands robust assessment tools for the monitoring of efficacy over time. Such tools are limited. We have previously highlighted the utility of the GaitRite system in MPS II where we showed abnormalities in gait. In this follow-up study we report the change in gait after 6 years of ERT. Six patients (three with neurological involvement) with MPS II formed the study group. The assessment of patients was performed using the GaitRite system, an electronic pressure sensitive walkway system which can identify changes in gait pattern through the course of the disease. Patients have been assessed at baseline and sequentially following the administration of ERT. Each boy walked at preferred speed and data was collected from 4 consecutive passes on the GaitRite mat. Individual characteristics of gait, such as velocity, step length and base of support have been assessed. Alterations in the studied parameters have been analysed
UN
S19
Outcomes from 5 years of treatment with agalsidase alfa enzyme replacement therapy (ERT) for Fabry disease in patients enrolled in the Fabry Outcomes Survey (FOS) were compared with published findings for untreated patients with Fabry disease.1,2,3 Data were extracted from FOS, a Shire-sponsored database, for comparison with data from three published studies. Outcomes evaluated were annualized for rate of change in estimated glomerular filtration rate (eGFR) and left ventricular mass indexed to height (LVMI) as well as time to and ages at a composite morbidity endpoint and at death. FOS data were extracted for 740 treated patients who were followed for a median of approximately 5 years. Compared with no treatment, patients treated with agalsidase alfa demonstrated slower decline in renal function and slower progression of left ventricular hypertrophy. Male treated patients with baseline eGFR b60 mL/min/1.73 m2 had a mean (standard error of the mean [SEM]) annualized change in eGFR of − 2.86 (0.53) mL/min/1.73 m2/y compared with −6.8 (1.5) in the published untreated cohort. The mean (SEM) rate of LVMI increase with treatment was 0.33 (0.10) g/m2.7/y in males and 0.48 (0.09) in females, compared with 4.07 (1.03) in untreated males and 2.31 (0.81) in untreated females. Morbidity occurred later in treated patients, with ~ 15% risk after 24 months with ERT versus ~45% risk without treatment, with first events and deaths also occurring at older ages in patients administered ERT (e.g., estimated 50% risk at 77.5 years versus 60 years in males). Findings from these retrospective comparisons of observational data and published literature