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Ear, nose and throat and hernia surgeries in children with Hunter syndrome: Data from the Hunter Outcome Survey (HOS)
Abstracts / Molecular Genetics and Metabolism 114 (2015) S11–S130
doi:10.1016/j.ymgme.2014.12.179
177 Newborn screening of Pompe disease in Japan: 2 years experience Ken Momosaki, Shinichiro Yoshida, Shirou Matsumoto, Kimitoshi Nakamura, Hiroshi Mitsubuchi, Fumio Endo, Kumamoto University, Kumamoto, Japan
CO
RR
EC
TE
DP
Background: The high incidence (3.3–3.9%) of acid α-glucosidase pseudodeficiency, c. [1726G N A; 2065G N A] homozygote (AA homozygote), in Asian populations complicates newborn mass screening for Pompe disease. Barium hydroxide/zinc sulfate method (Ba/Zn method) was developed to improve the enzymatic diagnosis of Pompe disease in dried blood spots (DBS) by the hemoglobin elimination on 4MU detection. With a purpose in this study, we examined the effectiveness of Ba/Zn method on newborn screening (NBS) of Pompe disease in Japan. Method: We screened 21,107 DBS from the NBS program in Kumamoto, Japan from April 2013 to June 2014. We assayed A α-Glu activity in DBS with two different methods; 4-methylumbelliferone (4-MU) method and Ba/Zn method. Definitive diagnosis was done by the measurement of A α-Glu activity in fibroblasts using glycogen as substrate and genetic testing. Results: A total of 45 (0.21%) newborns were recalled for second DBS with low enzyme activity. The recall rate was significantly decreased from 1.66% to 0.21% using the Ba/Zn method instead of 4-MU method. A α-Glu activity in fibroblasts was carried out for 12 samples with abnormally low enzyme activity, revealed 5 Pompe patients. Conclusions: The Ba/Zn method has been validated as a more efficient tool than the 4-MU method in Asian populations because of high frequency of pseudodeficiency. For later-onset Pompe disease, it is necessary to explore new biomarkers for definitive diagnosis.
Somatic signs and symptoms of Hunter syndrome (mucopolysaccharidosis type II, MPS II, OMIM 309900), including ear, nose and throat (ENT) manifestations and umbilical and inguinal hernias, typically become apparent at 2–4 years of age. Many patients, however, experience a delay between the onset of symptoms and a diagnosis of Hunter syndrome. A previous study investigated the surgical histories of a patient population with Hunter syndrome (N = 527) in the Hunter Outcome Survey (HOS, a global, multicentre, longitudinal, observational registry) and found that over 80% of patients underwent surgical intervention at an early age (median, 2.6 years), often before diagnosis of Hunter syndrome (1). In addition, certain surgical interventions (particularly tympanostomy, hernia repair and carpal tunnel decompression) were performed more frequently in patients with Hunter syndrome than in the general population. The aims of this analysis were to assess the histories of ENT interventions and hernia repair procedures in patients with Hunter syndrome and to investigate patterns of these surgeries performed before diagnosis that could prompt consideration of Hunter syndrome. As of January 2014, surgical data were available for 784 patients in HOS; the median age of symptom onset was 1.5 years (n = 640) and the median age of Hunter syndrome diagnosis was 3.2 years (n = 744). Surgical interventions were performed between birth and last recorded clinic visit in 86.0% of patients (median age at first surgery, 2.7 years). The most common ENT surgery was tympanostomy (51.9% of patients; median age at first tympanostomy, 3.1 years), followed by adenoidectomy (50.1%; 3.3 years), tonsillectomy (36.4%; 4.3 years) and tracheotomy (5.0%; 12.1 years) (Table 1). Inguinal or umbilical hernias occurred in 75.8% of patients (586/773), and hernia repair was performed in 49.2% of patients (386/784), at a median age of 2.9 years). The first surgical intervention preceded diagnosis in 53.4% of patients who underwent surgical intervention at any time (327/612). Of the patients who needed surgery before diagnosis, 50.2% (164/327) underwent two or more types of surgery. The most frequent combinations of procedures were adenoidectomy and tympanostomy only (16.5% of patients who underwent more than one surgery; 27/164); adenoidectomy, tympanostomy and hernia repair (11.0%; 18/164); adenoidectomy and hernia repair (9.8%; 16/164); adenoidectomy, tympanostomy and tonsillectomy (9.1%; 15/164); adenoidectomy and tonsillectomy (8.5%; 14/164); and adenoidectomy, tympanostomy, hernia repair and tonsillectomy (7.9%; 13/164). This analysis of data in HOS shows that a large proportion of patients with Hunter syndrome undergoes surgical interventions, including ENT procedures and hernia repair, before diagnosis. Evaluation of surgical history and certain patterns of multiple ENT and hernia surgeries at a young age could therefore aid early diagnosis of Hunter syndrome. Funding information: Shire sponsors and funds the Hunter Outcome Survey. Medical writing support was provided by Dr. Ruth Gandolfo of Oxford PharmaGenesis™ Ltd. (Oxford, UK) and funded by Shire. Reference: 1. Mendelsohn NJ, Harmatz P, Bodamer O et al. Genet Med 2010; 12:816-22.
OF
available, improvements from baseline in bone parameters seen during the PAP continued during the 9-month extension period, with mean changes in total BMB = −2.15, lumbar spine T-score = +0.19, and lumbar spine Z-score = +0.26. For the 20 patients who switched from placebo to eliglustat during the extension phase, the mean changes from baseline after 9 months of eliglustat were total BMB = −0.94, lumbar spine T-score = +0.03, and lumbar spine Z-score = +0.03. No new safety concerns were identified. ENGAGE met its primary and secondary efficacy endpoints in the PAP. Placebo cross-over patients showed improvements during the extension period similar to those of the eliglustat-treated patients during the PAP. Patients who received eliglustat for 18 months continued to improve in all disease parameters beyond the initial 9-month PAP.
RO
S82
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doi:10.1016/j.ymgme.2014.12.180
178 Ear, nose and throat and hernia surgeries in children with Hunter syndrome: Data from the Hunter Outcome Survey (HOS) Isabelle Morina, Nancy Mendelsohnb, Barbara Burtonc, Simon A. Jonesd, Christina Lampee, David Molterf, aCytel, Inc., Geneva, Switzerland, b Children's Hospitals and Clinics of Minnesota, Minneapolis, MN, USA, c Ann & Robert H. Lurie Children’s Hospital, Northwestern University, Chicago, IL, USA, dManchester Centre for Genomic Medicine, St. Mary's Hospital, Manchester Academic Health Sciences Centre, Manchester, UK, e Horst Schmidt Clinic, Wiesbaden, Germany, fWashington University School of Medicine, St. Louis, MO, USA
doi:10.1016/j.ymgme.2014.12.181
doi:10.1016/j.ymgme.2014.12.179
177 Newborn screening of Pompe disease in Japan: 2 years experience Ken Momosaki, Shinichiro Yoshida, Shirou Matsumoto, Kimitoshi Nakamura, Hiroshi Mitsubuchi, Fumio Endo, Kumamoto University, Kumamoto, Japan
CO
RR
EC
TE
DP
Background: The high incidence (3.3–3.9%) of acid α-glucosidase pseudodeficiency, c. [1726G N A; 2065G N A] homozygote (AA homozygote), in Asian populations complicates newborn mass screening for Pompe disease. Barium hydroxide/zinc sulfate method (Ba/Zn method) was developed to improve the enzymatic diagnosis of Pompe disease in dried blood spots (DBS) by the hemoglobin elimination on 4MU detection. With a purpose in this study, we examined the effectiveness of Ba/Zn method on newborn screening (NBS) of Pompe disease in Japan. Method: We screened 21,107 DBS from the NBS program in Kumamoto, Japan from April 2013 to June 2014. We assayed A α-Glu activity in DBS with two different methods; 4-methylumbelliferone (4-MU) method and Ba/Zn method. Definitive diagnosis was done by the measurement of A α-Glu activity in fibroblasts using glycogen as substrate and genetic testing. Results: A total of 45 (0.21%) newborns were recalled for second DBS with low enzyme activity. The recall rate was significantly decreased from 1.66% to 0.21% using the Ba/Zn method instead of 4-MU method. A α-Glu activity in fibroblasts was carried out for 12 samples with abnormally low enzyme activity, revealed 5 Pompe patients. Conclusions: The Ba/Zn method has been validated as a more efficient tool than the 4-MU method in Asian populations because of high frequency of pseudodeficiency. For later-onset Pompe disease, it is necessary to explore new biomarkers for definitive diagnosis.
Somatic signs and symptoms of Hunter syndrome (mucopolysaccharidosis type II, MPS II, OMIM 309900), including ear, nose and throat (ENT) manifestations and umbilical and inguinal hernias, typically become apparent at 2–4 years of age. Many patients, however, experience a delay between the onset of symptoms and a diagnosis of Hunter syndrome. A previous study investigated the surgical histories of a patient population with Hunter syndrome (N = 527) in the Hunter Outcome Survey (HOS, a global, multicentre, longitudinal, observational registry) and found that over 80% of patients underwent surgical intervention at an early age (median, 2.6 years), often before diagnosis of Hunter syndrome (1). In addition, certain surgical interventions (particularly tympanostomy, hernia repair and carpal tunnel decompression) were performed more frequently in patients with Hunter syndrome than in the general population. The aims of this analysis were to assess the histories of ENT interventions and hernia repair procedures in patients with Hunter syndrome and to investigate patterns of these surgeries performed before diagnosis that could prompt consideration of Hunter syndrome. As of January 2014, surgical data were available for 784 patients in HOS; the median age of symptom onset was 1.5 years (n = 640) and the median age of Hunter syndrome diagnosis was 3.2 years (n = 744). Surgical interventions were performed between birth and last recorded clinic visit in 86.0% of patients (median age at first surgery, 2.7 years). The most common ENT surgery was tympanostomy (51.9% of patients; median age at first tympanostomy, 3.1 years), followed by adenoidectomy (50.1%; 3.3 years), tonsillectomy (36.4%; 4.3 years) and tracheotomy (5.0%; 12.1 years) (Table 1). Inguinal or umbilical hernias occurred in 75.8% of patients (586/773), and hernia repair was performed in 49.2% of patients (386/784), at a median age of 2.9 years). The first surgical intervention preceded diagnosis in 53.4% of patients who underwent surgical intervention at any time (327/612). Of the patients who needed surgery before diagnosis, 50.2% (164/327) underwent two or more types of surgery. The most frequent combinations of procedures were adenoidectomy and tympanostomy only (16.5% of patients who underwent more than one surgery; 27/164); adenoidectomy, tympanostomy and hernia repair (11.0%; 18/164); adenoidectomy and hernia repair (9.8%; 16/164); adenoidectomy, tympanostomy and tonsillectomy (9.1%; 15/164); adenoidectomy and tonsillectomy (8.5%; 14/164); and adenoidectomy, tympanostomy, hernia repair and tonsillectomy (7.9%; 13/164). This analysis of data in HOS shows that a large proportion of patients with Hunter syndrome undergoes surgical interventions, including ENT procedures and hernia repair, before diagnosis. Evaluation of surgical history and certain patterns of multiple ENT and hernia surgeries at a young age could therefore aid early diagnosis of Hunter syndrome. Funding information: Shire sponsors and funds the Hunter Outcome Survey. Medical writing support was provided by Dr. Ruth Gandolfo of Oxford PharmaGenesis™ Ltd. (Oxford, UK) and funded by Shire. Reference: 1. Mendelsohn NJ, Harmatz P, Bodamer O et al. Genet Med 2010; 12:816-22.
OF
available, improvements from baseline in bone parameters seen during the PAP continued during the 9-month extension period, with mean changes in total BMB = −2.15, lumbar spine T-score = +0.19, and lumbar spine Z-score = +0.26. For the 20 patients who switched from placebo to eliglustat during the extension phase, the mean changes from baseline after 9 months of eliglustat were total BMB = −0.94, lumbar spine T-score = +0.03, and lumbar spine Z-score = +0.03. No new safety concerns were identified. ENGAGE met its primary and secondary efficacy endpoints in the PAP. Placebo cross-over patients showed improvements during the extension period similar to those of the eliglustat-treated patients during the PAP. Patients who received eliglustat for 18 months continued to improve in all disease parameters beyond the initial 9-month PAP.
RO
S82
UN
doi:10.1016/j.ymgme.2014.12.180
178 Ear, nose and throat and hernia surgeries in children with Hunter syndrome: Data from the Hunter Outcome Survey (HOS) Isabelle Morina, Nancy Mendelsohnb, Barbara Burtonc, Simon A. Jonesd, Christina Lampee, David Molterf, aCytel, Inc., Geneva, Switzerland, b Children's Hospitals and Clinics of Minnesota, Minneapolis, MN, USA, c Ann & Robert H. Lurie Children’s Hospital, Northwestern University, Chicago, IL, USA, dManchester Centre for Genomic Medicine, St. Mary's Hospital, Manchester Academic Health Sciences Centre, Manchester, UK, e Horst Schmidt Clinic, Wiesbaden, Germany, fWashington University School of Medicine, St. Louis, MO, USA
doi:10.1016/j.ymgme.2014.12.181