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Non-neuronopathic Gaucher disease: a retrospective review comparing therapeutic outcomes of 2-week and 4-week enzyme replacement therapy
Abstracts / Molecular Genetics and Metabolism 120 (2016) S17–S145
Hurler syndrome (mucopolysaccharidosis IH) is an autosomal recessive disorder resulting from deficiency of lysosomal alpha-Liduronidase, causing systemic accumulation of glucosaminoglycans heparan sulfate and dermatan sulfate. Both sensorineural and conductive hearing loss have been described in Hurler syndrome. Etiologies of conductive hearing loss include chronic and recurrent otitis media and ossicular chain abnormalities. Otopathology studies have demonstrated decreased cochlear hair cells in temporal bones from individuals with Hurler syndrome. The transplant database at our institution was queried for pediatric patients who underwent hematopoietic stem cell transplant for Hurler syndrome between 1/2006 and 6/2015. Inclusion criteria were diagnosis of Hurler syndrome, history of hematopoietic stem cell transplant and documentation of auditory brainstem response testing prior to transplant. Twelve of 38 children met inclusion criteria. Charts were reviewed and data was extracted according to predefined variables. Subjects were diagnosed with Hurler syndrome at mean age 11.4 +/- 6.3 months. 50% were female. All subjects underwent pressure equalization tube placement. Auditory brainstem response testing showed bilateral sensorineural hearing loss in 6/12 subjects: four mild, one mild-moderate and one moderate. Normal hearing was identified in 2/12, unspecified mild hearing loss in 2/12, mild mixed hearing loss in 1/12, and unilateral mild single frequency hearing loss in 1/12. 7/12 subjects underwent repeat auditory brainstem response testing between three and twelve months after transplant. Of two subjects with normal pre-transplant hearing, one remained stable and one developed mild unilateral sensorineural hearing loss. Of four with mild pre-transplant hearing loss, one remained stable, one worsened (mild unilateral to mild bilateral), and two improved to normal hearing. One subject with moderate bilateral pre-transplant hearing loss improved to unilateral mild hearing loss. Findings illustrate the importance of audiologic and otolaryngologic evaluation in comprehensive management of MPS IH and suggest directions for future research.
S113
Fabry disease is a progressive, X-linked disorder caused by GLA mutations that reduce α-galactosidase A activity. Subsequent globotriaosylceramide (GL-3) accumulation in a wide variety of cell types leads to organ dysfunction. This study (NCT00701415) evaluated the efficacy and safety of two agalsidase beta low-dose regimens, 0.5 mg/kg every 2 weeks (0.5q2w, n=16) and 1.0 mg/kg every 4 weeks (1.0q4w, n=15) in 5-18-years-old male Fabry patients without clinically evident vital-organ involvement. The primary outcome was GL-3 clearance from the superficial skin capillary endothelium (SSCE). Skin biopsies at baseline and years 1, 3, and 5 were available for 29/31 boys (including 2 who received dose increases for clinical deterioration; excluding 2 drop-outs). Of 20 patients with a nonzero SSCE GL-3 score at baseline, 13 (65%) reached and maintained zero scores (7 on 0.5q2w, 6 on 1.0q4w). Shifts from baseline nonzero to zero SSCE GL-3 scores were statistically significant at each time point in the study population overall and both treatment groups, except at year 5 in the 1.0q4w group. Of 7 patients with baseline zero score, one had nonzero scores at low dose (1.0q4w). Patients with the highest peak anti-αgalactosidase IgG titers tended to show less robust GL-3 clearance. Two patients with dose increases to 1.0 mg/kg q2w (labeled dose) showed complete and sustained SSCE GL-3 clearance, despite one of them having the highest peak IgG titer. In summary, low-dose agalsidase beta had some efficacy in clearing GL-3 from SSCE, but results across patients were not uniform compared with those seen with agalsidase beta at 1.0 mg/kg q2w (Germain et al. 2007, Wraith et al. 2008); results were similar to observations from a low-dose agalsidase beta study (0.3 mg/kg q2w) in adults (Lubanda et al. 2009), suggesting a dose-response effect for agalsidase beta in Fabry disease. (Funding (study and abstract): Sanofi Genzyme.) doi:10.1016/j.ymgme.2016.11.290
doi:10.1016/j.ymgme.2016.11.289
281 A randomized, phase 3B, open-label, parallel-group study of agalsidase beta in treatment-naive male pediatric patients with Fabry disease without severe symptoms (FIELD study): GL-3 clearance from superficial skin capillary endothelium Uma Ramaswamia, Frits A Wijburgb, Daniel G Bichetc, Lorne A Clarked, Gabriela Dostalovae, Alejandro Fainboimf, Andreas Fellgiebelg, Cassiano Forcelinih, Kristina An Haacki, Robert J Hopkinj, Michael Mauerk, Behzad Najafiank, C. Ronald Scottl, Suma P Shankarm, Beth L Thurbergn, Camilla Tøndelo, Anna Tylki-Szymanskap, Bernard Bénichouq, aRoyal Free London NHS Foundation Trust, University College of London, London, United Kingdom, bAcademic Medical Center, University Hospital of Amsterdam, Amsterdam, Netherlands, cHôpital du Sacré-Coeur de Montréal, and University of Montreal, Montreal, QC, Canada, dUniversity of British Columbia, Child and Family Research Institute, Vancouver, BC, Canada, e Charles University Prague, General University Hospital Prague, Prague, Czech Republic, fHospital de Niños Ricardo Gutierrez, Hospital de Dia Polivalente, Buenos Aires, Argentina, gRheinhessen-Fachklinik Alzey, Alzey, Germany, hHospital São Vicente de Paulo, Passo Fundo, RS, Brazil, iSanofi Genzyme, Chilly-Mazarin, France, jCincinnati Children's Hospital Medical Center, and University of Cincinnati College Medicine, Cincinnati, OH, United States, kUniversity of Minnesota, Minneapolis, MN, United States, l University of Washington, Seattle, WA, United States, mEmory University School of Medicine, Decatur, GA, United States, nSanofi Genzyme, Framingham, MA, United States, oHaukeland University Hospital, Bergen, Norway, pKlinika Pediatrii, Żywienia I Chorób Metabolicznych Instytut “Pomnik – Centrum Zdrowia Dziecka”, Warsaw, Poland, qSanofi Genzyme, Saint-Germain-en-Laye, Cedex, France
282 Non-neuronopathic Gaucher disease: a retrospective review comparing therapeutic outcomes of 2-week and 4-week enzyme replacement therapy Uma Ramaswami, Hannah Heales, Niamh Finnegan, Mark Mckie, Derralynn Hughes, Atul Mehta, Royal Free London Hospital NHS Foundation Trust, London, United Kingdom Current approved therapy for non-neuronopathic Gaucher disease (GD; OMIMM 230800) includes every other week (EOW) enzyme replacement therapy (ERT). We compared achievement of therapeutic goals of EOW ERT with a 4 weekly dosing regimen of ERT (imiglucerase or velaglucerase alfa). Single centre, retrospective review of 19 patients stable on standard EOW ERT, switched to a 4 weekly regimen.14/19 with complete data were analysed. 9/14 doubled EOW dose, maintaining same total 4 weekly doses (group I). 5/14 in whom clinical manifestations were considered mild, 4 weekly doses had a reduction by 25-50% (group II). ERT dose in units/kg/EOW pre switch: median (range): 16.6(6.5 -25.6); 21.6(17.8 -30.8) in Groups I and II respectively. Platelets, serum ferritin, haemoglobin (Hb) and chitotriosidase were measured (a)pre switch; (b)9 months (±3 months) post switch; (c)2-3 years post switch. 8/14 on imiglucerase and 6/14 on velaglucerase alfa, median age at start of therapy 34.4 years(6.5- 54.2) and 54 years(19.2 69.30) respectively. All patients remained on the same ERT preparation post switch. Pre-switch ERT duration was 9.7 years(0.8 -18.8 years). 5/14 patients were splenectomised. Haematological parameters showed no significant change pre and post switch. In group I, chitotriosidase increased variably post switch: (a): 516 (99-2484); (b): 572 (1723956); (c) 1057 (96 -10105) respectively (p values ns). In group II, chitotriosidase remained stable post switch. No significant differences
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Abstracts / Molecular Genetics and Metabolism 120 (2016) S17–S145
noted according to splenectomy or ERT preparation. Quality of life questionnaires revealed 14/14 switched owing to convenience. 0/14 reported any deterioration in symptoms after switch. Following switch to 4 weekly ERT, in group I, chitotriosidase variably increased. In group II, in whom chitotriosidase was stable post switch, an individualised approach with lowering of total daily dose was possible. Regular assessment of haematinics and chitotriosidase in conjunction with patients’ needs and quality of life is recommended when switching from EOW ERT.
no significant development of glomerulosclerosis or interstitial fibrosis. In summary, despite absence of renal function abnormalities, kidney cellular injury was present at baseline. Low-dose agalsidase beta regimens appeared sufficient to clear GL-3 from most renal cell types examined but, in contrast with standard agalsidase beta dose (Tøndel et al. 2013, Najafian et al. 2016), GL-3 was reduced in podocytes in some patients while accumulating in others. These observations suggest that podocyte GL-3 clearance is agalsidase beta dose-dependent and is important to consider in the clinical management of pediatric patients. (Funding study and abstract: Sanofi Genzyme.)
doi:10.1016/j.ymgme.2016.11.291 doi:10.1016/j.ymgme.2016.11.292 283 A randomized, phase 3B, open-label, parallel-group study of agalsidase beta in treatment-naive male pediatric patients with Fabry disease without severe symptoms (FIELD study): GL-3 clearance from kidney cells Uma Ramaswamia, Frits A Wijburgb, Daniel G Bichetc, Lorne A Clarked, Gabriela Dostalovae, Alejandro Fainboimf, Andreas Fellgiebelg, Cassiano Forcelinih, Kristina An Haacki, Robert J Hopkinj, Michael Mauerk, Behzad Najafiank, C. Ronald Scottl, Suma P Shankarm, Beth L Thurbergn, Camilla Tøndelo, Anna Tylki-Szymanskap, Bernard Bénichouq, aRoyal Free London NHS Foundation Trust, University College of London, London, United Kingdom, bAcademic Medical Center, University Hospital of Amsterdam, Amsterdam, Netherlands, cHôpital du Sacré-Coeur de Montréal and University of Montreal, Montreal, QC, Canada, dUniversity of British Columbia, Child and Family Research Institute, Vancouver, BC, Canada, e Charles University Prague, General University Hospital Prague, Prague, Czech Republic, fHospital de Niños Ricardo Gutierrez, Hospital de Dia Polivalente, Buenos Aires, Argentina, gRheinhessen-Fachklinik Alzey, Alzey, Germany, hHospital São Vicente de Paulo, Passo Fundo, RS, Brazil, iSanofi Genzyme, Chilly-Mazarin, France, jCincinnati Children's Hospital Medical Center, and University of Cincinnati College Medicine, Cincinnati, OH, United States, kUniversity of Minnesota, Minneapolis, MN, United States, lUniversity of Washington, Seattle, WA, United States, mEmory University School of Medicine, Decatur, GA, United States, nSanofi Genzyme, Framingham, MA, United States, oHaukeland University Hospital, Bergen, Norway, pKlinika Pediatrii, Żywienia I Chorób Metabolicznych Instytut “Pomnik – Centrum Zdrowia Dziecka”, Warsaw, Poland, qSanofi Genzyme, Saint-Germainen-Laye, Cedex, France Fabry disease is a progressive, X-linked disorder caused by reduced-to-absent α-galactosidase A activity and accumulation of globotriaosylceramide (GL-3) in multiple tissues, including the kidney. This study (NCT00701415) evaluated efficacy of two agalsidase beta lowdose regimens, 0.5 mg/kg/2 weeks (0.5q2w) and 1.0 mg/kg/4 weeks (1.0q4w), in 31 pediatric males without clinically evident vital-organ involvement. Exploratory outcomes included kidney GL-3 clearance and renal histology. Six patients had optional paired kidney biopsies (baseline, year 5). In an additional patient, a year 5 biopsy was compared with a 10 months pre-baseline biopsy. The baseline median age of patients who underwent biopsy was 15 (range 10-17) years. For endothelial cells (interstitial capillary, non-capillary, glomerular), mesangial and interstitial cells, and distal convoluted tubules/collecting ducts, nonzero baseline GL-3 scores shifted to zero in all patients at year 5 (semi-quantitative light microscopy). Absolute GL-3 inclusions volumes in podocytes (quantitative electron microscopy) decreased in 4 patients (3 on 0.5q2w, 1 on 1.0q4w) and increased in 3 (1 on 0.5q2w, 2 on 1.0q4w). Changes did not correlate with peak anti-α-galactosidase antibody titers (median 400, range: neg-12,800), kidney function, or podocyte injury. Fabry arteriopathy severity (estimate of fraction [%] of cortical arteriolar walls replaced by amorphous material) increased in 6 of 7 patients. There was
284 ConnectMPS: the global patient insights network for MPS, ML and related disorders Vanessa Rangel Millera, Mark Dantb, Jill Woodc, aPatientCrossroads, Bellevue, WA, United States, bThe National MPS Society, Durham, NC, United States, cJonah's Just Begun-Foundation to Cure Sanfilippo Inc., Brooklyn, NY, United States Mucopolysaccharidoses, mucolipidoses, and related glycoprotein storage disorders are ulta-rare lysosomal disorders with few treatments or effective therapies. Many treatments in preclinical or clinical development offer potential promise to patients struggling with these conditions. Recognizing the need to locate and collect insights reported directly from patients with all forms MPS and MLrelated disorders, we expanded the Sanfilippo syndrome registry to launch ConnectMPS (www.connectMPS.org) in July 2016, in partnership with the National MPS Society, ISMRD - The International Advocate for Glycoprotein Storage Diseases, and other related global advocacy organizations. Represented by 24+ organizations, the ConnectMPS patient insights network provides patients the ability to contribute medical data in a de-identified fashion using a secure online patient opt-in platform. Participants in the registry complete one or more surveys, longitudinally recorded, to capture diagnosis, current health, medical care, family history, and quality of life. The data de-identified and made available to the greater community through a dedicated online portal. Of 357 registrants, 326 (91%) have completed their account profile, and of those 63-78% have taken one or more available surveys. From the data, 224 participants report in general their health as Excellent-4%, Very good-24%, Good-40%, Fair24%, Poor-6%, or Participant is deceased-2%. Participants also report the following due to their condition (total = 241-245): admission to hospital (46%), visit to emergency room (38%), or surgery (34%). Patient report outcomes are valuable in improving the understanding of living with these rare lysosomal storage disorders, and the ConnectMPS network has proven a valuable, secure and patientcentric format for collecting this data for access by the broader community.
doi:10.1016/j.ymgme.2016.11.293
285 Novel LIPA mutations resulting in lysosomal acid lipase deficiency John Reyndersa, Barbara K. Burtonb, Guillermo del Angela, aAlexion Pharmaceuticals, Inc., New Haven, CT, United States, bNorthwestern University, Feinberg School of Medicine, Chicago, IL, United States
Hurler syndrome (mucopolysaccharidosis IH) is an autosomal recessive disorder resulting from deficiency of lysosomal alpha-Liduronidase, causing systemic accumulation of glucosaminoglycans heparan sulfate and dermatan sulfate. Both sensorineural and conductive hearing loss have been described in Hurler syndrome. Etiologies of conductive hearing loss include chronic and recurrent otitis media and ossicular chain abnormalities. Otopathology studies have demonstrated decreased cochlear hair cells in temporal bones from individuals with Hurler syndrome. The transplant database at our institution was queried for pediatric patients who underwent hematopoietic stem cell transplant for Hurler syndrome between 1/2006 and 6/2015. Inclusion criteria were diagnosis of Hurler syndrome, history of hematopoietic stem cell transplant and documentation of auditory brainstem response testing prior to transplant. Twelve of 38 children met inclusion criteria. Charts were reviewed and data was extracted according to predefined variables. Subjects were diagnosed with Hurler syndrome at mean age 11.4 +/- 6.3 months. 50% were female. All subjects underwent pressure equalization tube placement. Auditory brainstem response testing showed bilateral sensorineural hearing loss in 6/12 subjects: four mild, one mild-moderate and one moderate. Normal hearing was identified in 2/12, unspecified mild hearing loss in 2/12, mild mixed hearing loss in 1/12, and unilateral mild single frequency hearing loss in 1/12. 7/12 subjects underwent repeat auditory brainstem response testing between three and twelve months after transplant. Of two subjects with normal pre-transplant hearing, one remained stable and one developed mild unilateral sensorineural hearing loss. Of four with mild pre-transplant hearing loss, one remained stable, one worsened (mild unilateral to mild bilateral), and two improved to normal hearing. One subject with moderate bilateral pre-transplant hearing loss improved to unilateral mild hearing loss. Findings illustrate the importance of audiologic and otolaryngologic evaluation in comprehensive management of MPS IH and suggest directions for future research.
S113
Fabry disease is a progressive, X-linked disorder caused by GLA mutations that reduce α-galactosidase A activity. Subsequent globotriaosylceramide (GL-3) accumulation in a wide variety of cell types leads to organ dysfunction. This study (NCT00701415) evaluated the efficacy and safety of two agalsidase beta low-dose regimens, 0.5 mg/kg every 2 weeks (0.5q2w, n=16) and 1.0 mg/kg every 4 weeks (1.0q4w, n=15) in 5-18-years-old male Fabry patients without clinically evident vital-organ involvement. The primary outcome was GL-3 clearance from the superficial skin capillary endothelium (SSCE). Skin biopsies at baseline and years 1, 3, and 5 were available for 29/31 boys (including 2 who received dose increases for clinical deterioration; excluding 2 drop-outs). Of 20 patients with a nonzero SSCE GL-3 score at baseline, 13 (65%) reached and maintained zero scores (7 on 0.5q2w, 6 on 1.0q4w). Shifts from baseline nonzero to zero SSCE GL-3 scores were statistically significant at each time point in the study population overall and both treatment groups, except at year 5 in the 1.0q4w group. Of 7 patients with baseline zero score, one had nonzero scores at low dose (1.0q4w). Patients with the highest peak anti-αgalactosidase IgG titers tended to show less robust GL-3 clearance. Two patients with dose increases to 1.0 mg/kg q2w (labeled dose) showed complete and sustained SSCE GL-3 clearance, despite one of them having the highest peak IgG titer. In summary, low-dose agalsidase beta had some efficacy in clearing GL-3 from SSCE, but results across patients were not uniform compared with those seen with agalsidase beta at 1.0 mg/kg q2w (Germain et al. 2007, Wraith et al. 2008); results were similar to observations from a low-dose agalsidase beta study (0.3 mg/kg q2w) in adults (Lubanda et al. 2009), suggesting a dose-response effect for agalsidase beta in Fabry disease. (Funding (study and abstract): Sanofi Genzyme.) doi:10.1016/j.ymgme.2016.11.290
doi:10.1016/j.ymgme.2016.11.289
281 A randomized, phase 3B, open-label, parallel-group study of agalsidase beta in treatment-naive male pediatric patients with Fabry disease without severe symptoms (FIELD study): GL-3 clearance from superficial skin capillary endothelium Uma Ramaswamia, Frits A Wijburgb, Daniel G Bichetc, Lorne A Clarked, Gabriela Dostalovae, Alejandro Fainboimf, Andreas Fellgiebelg, Cassiano Forcelinih, Kristina An Haacki, Robert J Hopkinj, Michael Mauerk, Behzad Najafiank, C. Ronald Scottl, Suma P Shankarm, Beth L Thurbergn, Camilla Tøndelo, Anna Tylki-Szymanskap, Bernard Bénichouq, aRoyal Free London NHS Foundation Trust, University College of London, London, United Kingdom, bAcademic Medical Center, University Hospital of Amsterdam, Amsterdam, Netherlands, cHôpital du Sacré-Coeur de Montréal, and University of Montreal, Montreal, QC, Canada, dUniversity of British Columbia, Child and Family Research Institute, Vancouver, BC, Canada, e Charles University Prague, General University Hospital Prague, Prague, Czech Republic, fHospital de Niños Ricardo Gutierrez, Hospital de Dia Polivalente, Buenos Aires, Argentina, gRheinhessen-Fachklinik Alzey, Alzey, Germany, hHospital São Vicente de Paulo, Passo Fundo, RS, Brazil, iSanofi Genzyme, Chilly-Mazarin, France, jCincinnati Children's Hospital Medical Center, and University of Cincinnati College Medicine, Cincinnati, OH, United States, kUniversity of Minnesota, Minneapolis, MN, United States, l University of Washington, Seattle, WA, United States, mEmory University School of Medicine, Decatur, GA, United States, nSanofi Genzyme, Framingham, MA, United States, oHaukeland University Hospital, Bergen, Norway, pKlinika Pediatrii, Żywienia I Chorób Metabolicznych Instytut “Pomnik – Centrum Zdrowia Dziecka”, Warsaw, Poland, qSanofi Genzyme, Saint-Germain-en-Laye, Cedex, France
282 Non-neuronopathic Gaucher disease: a retrospective review comparing therapeutic outcomes of 2-week and 4-week enzyme replacement therapy Uma Ramaswami, Hannah Heales, Niamh Finnegan, Mark Mckie, Derralynn Hughes, Atul Mehta, Royal Free London Hospital NHS Foundation Trust, London, United Kingdom Current approved therapy for non-neuronopathic Gaucher disease (GD; OMIMM 230800) includes every other week (EOW) enzyme replacement therapy (ERT). We compared achievement of therapeutic goals of EOW ERT with a 4 weekly dosing regimen of ERT (imiglucerase or velaglucerase alfa). Single centre, retrospective review of 19 patients stable on standard EOW ERT, switched to a 4 weekly regimen.14/19 with complete data were analysed. 9/14 doubled EOW dose, maintaining same total 4 weekly doses (group I). 5/14 in whom clinical manifestations were considered mild, 4 weekly doses had a reduction by 25-50% (group II). ERT dose in units/kg/EOW pre switch: median (range): 16.6(6.5 -25.6); 21.6(17.8 -30.8) in Groups I and II respectively. Platelets, serum ferritin, haemoglobin (Hb) and chitotriosidase were measured (a)pre switch; (b)9 months (±3 months) post switch; (c)2-3 years post switch. 8/14 on imiglucerase and 6/14 on velaglucerase alfa, median age at start of therapy 34.4 years(6.5- 54.2) and 54 years(19.2 69.30) respectively. All patients remained on the same ERT preparation post switch. Pre-switch ERT duration was 9.7 years(0.8 -18.8 years). 5/14 patients were splenectomised. Haematological parameters showed no significant change pre and post switch. In group I, chitotriosidase increased variably post switch: (a): 516 (99-2484); (b): 572 (1723956); (c) 1057 (96 -10105) respectively (p values ns). In group II, chitotriosidase remained stable post switch. No significant differences
S114
Abstracts / Molecular Genetics and Metabolism 120 (2016) S17–S145
noted according to splenectomy or ERT preparation. Quality of life questionnaires revealed 14/14 switched owing to convenience. 0/14 reported any deterioration in symptoms after switch. Following switch to 4 weekly ERT, in group I, chitotriosidase variably increased. In group II, in whom chitotriosidase was stable post switch, an individualised approach with lowering of total daily dose was possible. Regular assessment of haematinics and chitotriosidase in conjunction with patients’ needs and quality of life is recommended when switching from EOW ERT.
no significant development of glomerulosclerosis or interstitial fibrosis. In summary, despite absence of renal function abnormalities, kidney cellular injury was present at baseline. Low-dose agalsidase beta regimens appeared sufficient to clear GL-3 from most renal cell types examined but, in contrast with standard agalsidase beta dose (Tøndel et al. 2013, Najafian et al. 2016), GL-3 was reduced in podocytes in some patients while accumulating in others. These observations suggest that podocyte GL-3 clearance is agalsidase beta dose-dependent and is important to consider in the clinical management of pediatric patients. (Funding study and abstract: Sanofi Genzyme.)
doi:10.1016/j.ymgme.2016.11.291 doi:10.1016/j.ymgme.2016.11.292 283 A randomized, phase 3B, open-label, parallel-group study of agalsidase beta in treatment-naive male pediatric patients with Fabry disease without severe symptoms (FIELD study): GL-3 clearance from kidney cells Uma Ramaswamia, Frits A Wijburgb, Daniel G Bichetc, Lorne A Clarked, Gabriela Dostalovae, Alejandro Fainboimf, Andreas Fellgiebelg, Cassiano Forcelinih, Kristina An Haacki, Robert J Hopkinj, Michael Mauerk, Behzad Najafiank, C. Ronald Scottl, Suma P Shankarm, Beth L Thurbergn, Camilla Tøndelo, Anna Tylki-Szymanskap, Bernard Bénichouq, aRoyal Free London NHS Foundation Trust, University College of London, London, United Kingdom, bAcademic Medical Center, University Hospital of Amsterdam, Amsterdam, Netherlands, cHôpital du Sacré-Coeur de Montréal and University of Montreal, Montreal, QC, Canada, dUniversity of British Columbia, Child and Family Research Institute, Vancouver, BC, Canada, e Charles University Prague, General University Hospital Prague, Prague, Czech Republic, fHospital de Niños Ricardo Gutierrez, Hospital de Dia Polivalente, Buenos Aires, Argentina, gRheinhessen-Fachklinik Alzey, Alzey, Germany, hHospital São Vicente de Paulo, Passo Fundo, RS, Brazil, iSanofi Genzyme, Chilly-Mazarin, France, jCincinnati Children's Hospital Medical Center, and University of Cincinnati College Medicine, Cincinnati, OH, United States, kUniversity of Minnesota, Minneapolis, MN, United States, lUniversity of Washington, Seattle, WA, United States, mEmory University School of Medicine, Decatur, GA, United States, nSanofi Genzyme, Framingham, MA, United States, oHaukeland University Hospital, Bergen, Norway, pKlinika Pediatrii, Żywienia I Chorób Metabolicznych Instytut “Pomnik – Centrum Zdrowia Dziecka”, Warsaw, Poland, qSanofi Genzyme, Saint-Germainen-Laye, Cedex, France Fabry disease is a progressive, X-linked disorder caused by reduced-to-absent α-galactosidase A activity and accumulation of globotriaosylceramide (GL-3) in multiple tissues, including the kidney. This study (NCT00701415) evaluated efficacy of two agalsidase beta lowdose regimens, 0.5 mg/kg/2 weeks (0.5q2w) and 1.0 mg/kg/4 weeks (1.0q4w), in 31 pediatric males without clinically evident vital-organ involvement. Exploratory outcomes included kidney GL-3 clearance and renal histology. Six patients had optional paired kidney biopsies (baseline, year 5). In an additional patient, a year 5 biopsy was compared with a 10 months pre-baseline biopsy. The baseline median age of patients who underwent biopsy was 15 (range 10-17) years. For endothelial cells (interstitial capillary, non-capillary, glomerular), mesangial and interstitial cells, and distal convoluted tubules/collecting ducts, nonzero baseline GL-3 scores shifted to zero in all patients at year 5 (semi-quantitative light microscopy). Absolute GL-3 inclusions volumes in podocytes (quantitative electron microscopy) decreased in 4 patients (3 on 0.5q2w, 1 on 1.0q4w) and increased in 3 (1 on 0.5q2w, 2 on 1.0q4w). Changes did not correlate with peak anti-α-galactosidase antibody titers (median 400, range: neg-12,800), kidney function, or podocyte injury. Fabry arteriopathy severity (estimate of fraction [%] of cortical arteriolar walls replaced by amorphous material) increased in 6 of 7 patients. There was
284 ConnectMPS: the global patient insights network for MPS, ML and related disorders Vanessa Rangel Millera, Mark Dantb, Jill Woodc, aPatientCrossroads, Bellevue, WA, United States, bThe National MPS Society, Durham, NC, United States, cJonah's Just Begun-Foundation to Cure Sanfilippo Inc., Brooklyn, NY, United States Mucopolysaccharidoses, mucolipidoses, and related glycoprotein storage disorders are ulta-rare lysosomal disorders with few treatments or effective therapies. Many treatments in preclinical or clinical development offer potential promise to patients struggling with these conditions. Recognizing the need to locate and collect insights reported directly from patients with all forms MPS and MLrelated disorders, we expanded the Sanfilippo syndrome registry to launch ConnectMPS (www.connectMPS.org) in July 2016, in partnership with the National MPS Society, ISMRD - The International Advocate for Glycoprotein Storage Diseases, and other related global advocacy organizations. Represented by 24+ organizations, the ConnectMPS patient insights network provides patients the ability to contribute medical data in a de-identified fashion using a secure online patient opt-in platform. Participants in the registry complete one or more surveys, longitudinally recorded, to capture diagnosis, current health, medical care, family history, and quality of life. The data de-identified and made available to the greater community through a dedicated online portal. Of 357 registrants, 326 (91%) have completed their account profile, and of those 63-78% have taken one or more available surveys. From the data, 224 participants report in general their health as Excellent-4%, Very good-24%, Good-40%, Fair24%, Poor-6%, or Participant is deceased-2%. Participants also report the following due to their condition (total = 241-245): admission to hospital (46%), visit to emergency room (38%), or surgery (34%). Patient report outcomes are valuable in improving the understanding of living with these rare lysosomal storage disorders, and the ConnectMPS network has proven a valuable, secure and patientcentric format for collecting this data for access by the broader community.
doi:10.1016/j.ymgme.2016.11.293
285 Novel LIPA mutations resulting in lysosomal acid lipase deficiency John Reyndersa, Barbara K. Burtonb, Guillermo del Angela, aAlexion Pharmaceuticals, Inc., New Haven, CT, United States, bNorthwestern University, Feinberg School of Medicine, Chicago, IL, United States