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Clinical features and outcomes in multiple sulfatase deficiency: A single centre experience
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Abstracts / Molecular Genetics and Metabolism 117 (2016) S14–S124
287 Hearing loss in mucopolysaccharidosis and its impact on quality of life; A review of the literature Archana Soni-Jaiswala, Simon A. Jonesa, Peter Calleryb, Iain A. Brucea, a Central Manchester Teaching Hospitals NHS Trust, Manchester, United Kingdom, bUniversity of Manchester, Manchester, United Kingdom Traditionally, preserving life has been the central focus of clinical intervention and research effort in the mucoploysaccharidosis (MPS). Hematopoietic stem cell transplantation and enzyme replacement therapy are now established in clinical practice and have led to an increase in life expectancy. Improvement in long-term prognosis has naturally led to greater emphasis being placed upon quality of life issues in patients with MPS. Sensory deficits in MPS disease have traditionally been considered of secondary importance to the other manifestations of the disease, and this is reflected in the paucity of information available to guide clinical practice. Hearing loss is a universal finding in MPS with a third of patients suffering with severe to profound loss. The hearing loss may be conductive, secondary to otitis media with effusion, sensorineural or mixed. In many children, this occurs in conjunction with neurocognitive disease and other sensory deficits such as poor eye sight. The hearing loss may contribute to delayed acquisition of language, difficult communication with peers, behaviour problems and the need for special needs education. Children may struggle to cope with repeat insertion of ventilation tubes or the practicality of wearing hearing aids. We present a review of the literature, identifying the incidence, pathogenesis and impact of hearing loss on the quality of life of children with MPS. Patients with MPS are suitable candidates for implantable hearing aids, such as cochlear implants and bone conduction implants, should there hearing impairment not be ameliorated by more ‘conventional’ hearing solutions. There is an urgent unmet need to increase awareness of hearing loss in MPS disease and develop a strong evidence base. doi:10.1016/j.ymgme.2015.12.445
288 Mucopolysaccharidosis I: Parental beliefs about the impact of disease on the quality of life of their children Archana Soni-Jaiswala, Jean Mercera, Simon A. Jonesa, Iain A. Brucea, Peter Calleryb, aCentral Manchester University Hospitals NHS Trust, Manchester, United Kingdom, bUniversity of Manchester, Manchester, United Kingdom Hematopoietic stem cell transplants, alongside enzyme replacement therapy and good multi-disciplinary care, have dramatically improved the life expectancy in children with MPS I, with better objective and functional outcomes. Despite these improvements, children with both the attenuated (non-Hurler) and severe (Hurler) variants of the disease have marked residual morbidity. As part of their multi-system disease, they develop head and neck disease including obstructive sleep apnoea (OSA) and hearing loss. This exploratory qualitative study explores the impact of head and neck disease, alongside the impact of MPS I as a whole, on the quality of life of affected children and their parents. A grounded theory approach was used to conduct this study. Children and their parents were invited to participate in semi-structured, interviews, designed to explore the above. The transcribed interviews were coded and emergent themes explored until saturation occurred. The families of eleven children with MPS I were interviewed, five with Hurler’s and six with the attenuated non-Hurler’s. Important themes to emerge
were the parental fear that their child might die due to the OSA and the impact of this on their emotional well-being. Parents also felt that the delayed acquisition of language contributed to communication difficulties for their children, resulting in loss of confidence and behaviour problems. For parents these themes had the biggest impact on their child’s quality of life. Children themselves spoke of chronic pain; restricted mobility; physical difference; restricted participation in social activities such as sports secondary, all secondary to their musculoskeletal disease burden. For the children this had the biggest impact on their quality of life. Parents and children with MPS I worried about ‘fitting-in’ with broader society. doi:10.1016/j.ymgme.2015.12.446
289 One-year data from the Space4u2talk Emotional Well-being Programme Rebecca C. Southalla, Chris Hendriksza, Alan Naughtonb, Louise M. Ellisb, aSalford Royal NHS Trust Hospital, Manchester, United Kingdom, b SPACE4U2TALK, Lichfield, United Kingdom Space4u2talk, is a 3 year pilot project trialling a secondary care specialist psychological therapy service to meet the emotional wellbeing needs of patients with metabolic disorders. In the first year 75 patients registered at Salford Royal Foundation NHS Trust Metabolic Disorders Unit self-referred or a health professional requested the service for them. Individual patients were triaged and then assigned to an intervention group in a stepped-care mode consisting of graded treatment from self-help at step 1 to psychiatric care at step 4. At step 2 and 3 patients were assigned to one to one evidence-based high-intensity talking therapy sessions. Individual weekly sessions, tailored for patients with long-term conditions, were offered face-to-face or via webcam, telephone, email or text. All patients had access to our specialist website containing self-help literature, computerised CBT, a moderated discussion forum and Peer Wellbeing Champions to provide mentoring support. Between September 2014 & 2015, 11 persons declined the service & 5 persons accepted guided self-help or cCBT at step 1 and 50 patients received talking therapy at step 2 or 3. 1 person was referred on to step 4. The mean number of sessions attended was 10 and 623 sessions were provided over a one year period, with only 5 sessions not attended. All patients showed measurable improvement in emotional wellbeing & quality of life as demonstrated by a drop of five points utilising validated tools - the PHQ, GAD & EQ5D Anxiety and Depression dimension. These excellent clinical outcomes, the exceptionally low DNA rate, a 97% satisfaction rating on the exit survey, further evidenced excellent service user engagement and benefits. First year data was used to augment program design for the second year for example to include group therapy for clusters of patients with the same metabolic condition and a cost-benefit analysis is ongoing. doi:10.1016/j.ymgme.2015.12.447
290 Clinical features and outcomes in multiple sulfatase deficiency: A single centre experience Srividya Sreekantam, Louis Simmons, Tim Hutchins, Evangeline Wassmer, Suresh Vijay, Julian Raiman, Saikat Santra, Birmingham Children's Hospital, Birmingham, United Kingdom
Abstracts / Molecular Genetics and Metabolism 117 (2016) S14–S124
Background: Multiple sulfatase deficiency (MSD) is a rare lysosomal disorder due to mutations in SUMF1 resulting in inactive sulfatases. To date there are very few cases reported in the literature. We report a series of 6 patients with MSD in our centre. Methods: Retrospective case note review of all patients diagnosed with MSD in our centre focussing on clinical phenotype, mutation analysis and disease outcomes. Results: 6 patients (4 males; 2 females) were diagnosed with MSD between 1998-2015. Mean age of presentation was 2.8 yrs with hypotonia, ataxia, developmental regression, icthyosis and visual impairment. 2/6 had congenital talipes. There was a mean 4.9 years delay from presentation to diagnosis in index cases. MSD was confirmed by enzymatic assay of two sulfatases in all and SUMF1 sequencing in 5/6 patients. Subsequent clinical problems included epilepsy (4/6), recurrent respiratory infections (3/6) and dysphagia requiring enteral feeding (5/6). One child died aged 10 yrs from respiratory failure. Contrary to published cases, no patient developed cardiomyopathy. Conclusion: Our study noted variable clinical course and outcomes in MSD. It is a lethal neurodegenerative condition with no cure. Early recognition is important to facilitate genetic counselling and prevention in future pregnancies. doi:10.1016/j.ymgme.2015.12.448
291 Cathepsin-mediated alterations in TGF-beta related signaling underlie the cartilage and bone defects associated with impaired lysosomal targeting Richard Steeta, Heather Flanagan-Steeta, Megan Aarnioa, Brian Kwana, Pierre Guihardb, Aaron Petreyc, Mark Haskinsd, Frederic Blanchardb, aUniversity of Georgia, Athens, GA, United States, bUniversity of Nantes, Nantes, France, cCleveland Clinic, Cleveland, OH, United States, d University of Pennsylvania, Philadelphia, PA, United States Hypersecretion of acid hydrolases is a hallmark feature of mucolipidosis II (ML II), a lysosomal disease caused by loss of carbohydrate-dependent lysosomal targeting. Inappropriate extracellular action of these hydrolases is thought to contribute to skeletal pathogenesis but the mechanisms that connect hydrolase activity to the onset of disease phenotypes remain poorly understood. Taking advantage of a zebrafish model for ML II, we previously showed that the cartilage morphogenesis defects in this model are associated with altered chondrocyte differentiation, excessive deposition of type II collagen and elevated activity of several cathepsin proteases including cathepsin K. Cathepsin K was localized to the extracellular space surrounding developing chondrocytes in ML II zebrafish embryos, indicating a requirement for mannose 6-phosphate dependent lysosomal sorting. Here we link extracellular cathepsin K activity to abnormal bone and cartilage development in ML II animals by demonstrating that it disrupts the balance of TGF-beta-related signaling during chondrogenesis. TGFbeta signaling is elevated while BMP signaling is reduced in both feline and zebrafish ML II chondrocytes and osteoblasts, maintaining these cells in an immature state. Reducing cathepsin K activity or expression of the transcriptional regulator Sox9a in ML II zebrafish significantly improved the observed phenotypes. We further identify components of the large latent TGF-beta complex as novel targets of cathepsin K at neutral pH, providing a possible mechanism for enhanced TGF-beta activation in vivo. These findings highlight the complexity of the skeletal disease associated with MLII and bring new insight to the role of secreted cathepsin proteases in cartilage development and growth factor regulation. doi:10.1016/j.ymgme.2015.12.449
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292 Pregnancy in individuals with mucopolysaccharidosis (MPS): A case series Fiona Stewarta, Paul Harmatzb, Elizabeth Braunlinc, Andrew Bentleyd, Barbara Burtone, Nathalie Guffonf, Susan Haleg, Tracey Johnstonh, Susanne Kircheri, Pavan Kochharj, John Mitchellk, Ursula Plöckingerl, Zlatko Sisicm, aBelfast City Hospital, Belfast, United Kingdom, bUCSF Benioff Children's Hospital, Oakland, CA, United States, cUniversity of Minnesota, Minnesota, MN, United States, dUniversity Hospital of South Manchester NHS Foundation Trust, Manchester, United Kingdom, eLurie Children's Hospital, Chicago, IL, United States, fHopital Femme Mere Enfants, Lyon, France, gSeattle Children's Hospital, Seattle, WA, United States, hBirmingham Women's NHS Foundation Trust, Birmingham, United Kingdom, iInstitute of Medical Chemistry and Institute of Medical Genetics, Medical University of Vienna, Austria, jCentral Manchester University Hospitals, Manchester, United Kingdom, kMontreal Children's Hospital, Montreal, QC, Canada, lCharite-Universitatsmedizin, Berlin, Germany, mBioMarin Europe Limited, London, United Kingdom Due to an increase in life expectancy, a growing group of MPS patients are reaching adulthood and may have children. The outcomes of 9 pregnancies in 8 women (1 MPS IHS, 3 MPS IVA, 1 MPS IVB, 3 MPS VI) and from 4 men (2 MPS II, 2 MPS IVA) with MPS, followed up at 6 different tertiary care centers in the US, UK, France, Austria, and Germany are discussed. Seven of the women with MPS had complications during pregnancy, including lumbar pain, migraine, gastric pain and reflux requiring treatment, high relative weight gain, frequent spotting at 18 weeks, hospitalization for atrial tachycardia, medication adjustment due to hypotension, and hyperemesis gravidarum resulting in intermittent hypothyroidism. Most women stopped working during pregnancy. Only 2 women had uncomplicated and full-term spontaneous vaginal deliveries. Seven deliveries (in 6 women) were planned cesarean sections, mostly due to a disproportion in size between child and mother. Delivery at 37 weeks was required in one case because of maternal aortic stenosis, atrial tachycardia, and a history of nocturnal seizures. One woman required a blood transfusion at delivery. After delivery, 1 woman developed mastitis and a breast abscess requiring emergency surgery and an umbilical hernia requiring surgical repair; 1 woman had deterioration of cardiac problems. Neonatal intensive care was required in 2 cases. All 4 pregnancies and deliveries of the male patients’ partners were uncomplicated. All children had normal growth and development. Overall, this case series shows that women with MPS have high-risk pregnancies and deliveries. Nevertheless, with adequate evaluation of potential risks, proper counselling, planning and regular follow-up in a center with tertiary level maternal and neonatal care, the outcome of most pregnancies seems favorable. The cases were presented at an advisory board meeting sponsored by BioMarin Pharmaceutical Inc. doi:10.1016/j.ymgme.2015.12.450
293 Management of fertility and pregnancy in individuals with mucopolysaccharidosis (MPS) Fiona Stewarta, Paul Harmatzb, Elizabeth Braunlinc, Andrew Bentleyd, Barbara Burtone, Nathalie Guffonf, Susan Haleg, Tracey Johnstonh, Susanne Kircheri, Pavan Kochharj, John Mitchellk, Ursula Plöckingerl, Jennifer Semotokm, Zlatko Sisicn, aBelfast City Hospital, Belfast, United Kingdom, bUCSF Benioff Children's Hospital, Oakland, CA, United States, c University of Minnesota, Minnesota, MN, United States, dUniversity Hospital of South Manchester NHS Foundation Trust, Manchester,
Abstracts / Molecular Genetics and Metabolism 117 (2016) S14–S124
287 Hearing loss in mucopolysaccharidosis and its impact on quality of life; A review of the literature Archana Soni-Jaiswala, Simon A. Jonesa, Peter Calleryb, Iain A. Brucea, a Central Manchester Teaching Hospitals NHS Trust, Manchester, United Kingdom, bUniversity of Manchester, Manchester, United Kingdom Traditionally, preserving life has been the central focus of clinical intervention and research effort in the mucoploysaccharidosis (MPS). Hematopoietic stem cell transplantation and enzyme replacement therapy are now established in clinical practice and have led to an increase in life expectancy. Improvement in long-term prognosis has naturally led to greater emphasis being placed upon quality of life issues in patients with MPS. Sensory deficits in MPS disease have traditionally been considered of secondary importance to the other manifestations of the disease, and this is reflected in the paucity of information available to guide clinical practice. Hearing loss is a universal finding in MPS with a third of patients suffering with severe to profound loss. The hearing loss may be conductive, secondary to otitis media with effusion, sensorineural or mixed. In many children, this occurs in conjunction with neurocognitive disease and other sensory deficits such as poor eye sight. The hearing loss may contribute to delayed acquisition of language, difficult communication with peers, behaviour problems and the need for special needs education. Children may struggle to cope with repeat insertion of ventilation tubes or the practicality of wearing hearing aids. We present a review of the literature, identifying the incidence, pathogenesis and impact of hearing loss on the quality of life of children with MPS. Patients with MPS are suitable candidates for implantable hearing aids, such as cochlear implants and bone conduction implants, should there hearing impairment not be ameliorated by more ‘conventional’ hearing solutions. There is an urgent unmet need to increase awareness of hearing loss in MPS disease and develop a strong evidence base. doi:10.1016/j.ymgme.2015.12.445
288 Mucopolysaccharidosis I: Parental beliefs about the impact of disease on the quality of life of their children Archana Soni-Jaiswala, Jean Mercera, Simon A. Jonesa, Iain A. Brucea, Peter Calleryb, aCentral Manchester University Hospitals NHS Trust, Manchester, United Kingdom, bUniversity of Manchester, Manchester, United Kingdom Hematopoietic stem cell transplants, alongside enzyme replacement therapy and good multi-disciplinary care, have dramatically improved the life expectancy in children with MPS I, with better objective and functional outcomes. Despite these improvements, children with both the attenuated (non-Hurler) and severe (Hurler) variants of the disease have marked residual morbidity. As part of their multi-system disease, they develop head and neck disease including obstructive sleep apnoea (OSA) and hearing loss. This exploratory qualitative study explores the impact of head and neck disease, alongside the impact of MPS I as a whole, on the quality of life of affected children and their parents. A grounded theory approach was used to conduct this study. Children and their parents were invited to participate in semi-structured, interviews, designed to explore the above. The transcribed interviews were coded and emergent themes explored until saturation occurred. The families of eleven children with MPS I were interviewed, five with Hurler’s and six with the attenuated non-Hurler’s. Important themes to emerge
were the parental fear that their child might die due to the OSA and the impact of this on their emotional well-being. Parents also felt that the delayed acquisition of language contributed to communication difficulties for their children, resulting in loss of confidence and behaviour problems. For parents these themes had the biggest impact on their child’s quality of life. Children themselves spoke of chronic pain; restricted mobility; physical difference; restricted participation in social activities such as sports secondary, all secondary to their musculoskeletal disease burden. For the children this had the biggest impact on their quality of life. Parents and children with MPS I worried about ‘fitting-in’ with broader society. doi:10.1016/j.ymgme.2015.12.446
289 One-year data from the Space4u2talk Emotional Well-being Programme Rebecca C. Southalla, Chris Hendriksza, Alan Naughtonb, Louise M. Ellisb, aSalford Royal NHS Trust Hospital, Manchester, United Kingdom, b SPACE4U2TALK, Lichfield, United Kingdom Space4u2talk, is a 3 year pilot project trialling a secondary care specialist psychological therapy service to meet the emotional wellbeing needs of patients with metabolic disorders. In the first year 75 patients registered at Salford Royal Foundation NHS Trust Metabolic Disorders Unit self-referred or a health professional requested the service for them. Individual patients were triaged and then assigned to an intervention group in a stepped-care mode consisting of graded treatment from self-help at step 1 to psychiatric care at step 4. At step 2 and 3 patients were assigned to one to one evidence-based high-intensity talking therapy sessions. Individual weekly sessions, tailored for patients with long-term conditions, were offered face-to-face or via webcam, telephone, email or text. All patients had access to our specialist website containing self-help literature, computerised CBT, a moderated discussion forum and Peer Wellbeing Champions to provide mentoring support. Between September 2014 & 2015, 11 persons declined the service & 5 persons accepted guided self-help or cCBT at step 1 and 50 patients received talking therapy at step 2 or 3. 1 person was referred on to step 4. The mean number of sessions attended was 10 and 623 sessions were provided over a one year period, with only 5 sessions not attended. All patients showed measurable improvement in emotional wellbeing & quality of life as demonstrated by a drop of five points utilising validated tools - the PHQ, GAD & EQ5D Anxiety and Depression dimension. These excellent clinical outcomes, the exceptionally low DNA rate, a 97% satisfaction rating on the exit survey, further evidenced excellent service user engagement and benefits. First year data was used to augment program design for the second year for example to include group therapy for clusters of patients with the same metabolic condition and a cost-benefit analysis is ongoing. doi:10.1016/j.ymgme.2015.12.447
290 Clinical features and outcomes in multiple sulfatase deficiency: A single centre experience Srividya Sreekantam, Louis Simmons, Tim Hutchins, Evangeline Wassmer, Suresh Vijay, Julian Raiman, Saikat Santra, Birmingham Children's Hospital, Birmingham, United Kingdom
Abstracts / Molecular Genetics and Metabolism 117 (2016) S14–S124
Background: Multiple sulfatase deficiency (MSD) is a rare lysosomal disorder due to mutations in SUMF1 resulting in inactive sulfatases. To date there are very few cases reported in the literature. We report a series of 6 patients with MSD in our centre. Methods: Retrospective case note review of all patients diagnosed with MSD in our centre focussing on clinical phenotype, mutation analysis and disease outcomes. Results: 6 patients (4 males; 2 females) were diagnosed with MSD between 1998-2015. Mean age of presentation was 2.8 yrs with hypotonia, ataxia, developmental regression, icthyosis and visual impairment. 2/6 had congenital talipes. There was a mean 4.9 years delay from presentation to diagnosis in index cases. MSD was confirmed by enzymatic assay of two sulfatases in all and SUMF1 sequencing in 5/6 patients. Subsequent clinical problems included epilepsy (4/6), recurrent respiratory infections (3/6) and dysphagia requiring enteral feeding (5/6). One child died aged 10 yrs from respiratory failure. Contrary to published cases, no patient developed cardiomyopathy. Conclusion: Our study noted variable clinical course and outcomes in MSD. It is a lethal neurodegenerative condition with no cure. Early recognition is important to facilitate genetic counselling and prevention in future pregnancies. doi:10.1016/j.ymgme.2015.12.448
291 Cathepsin-mediated alterations in TGF-beta related signaling underlie the cartilage and bone defects associated with impaired lysosomal targeting Richard Steeta, Heather Flanagan-Steeta, Megan Aarnioa, Brian Kwana, Pierre Guihardb, Aaron Petreyc, Mark Haskinsd, Frederic Blanchardb, aUniversity of Georgia, Athens, GA, United States, bUniversity of Nantes, Nantes, France, cCleveland Clinic, Cleveland, OH, United States, d University of Pennsylvania, Philadelphia, PA, United States Hypersecretion of acid hydrolases is a hallmark feature of mucolipidosis II (ML II), a lysosomal disease caused by loss of carbohydrate-dependent lysosomal targeting. Inappropriate extracellular action of these hydrolases is thought to contribute to skeletal pathogenesis but the mechanisms that connect hydrolase activity to the onset of disease phenotypes remain poorly understood. Taking advantage of a zebrafish model for ML II, we previously showed that the cartilage morphogenesis defects in this model are associated with altered chondrocyte differentiation, excessive deposition of type II collagen and elevated activity of several cathepsin proteases including cathepsin K. Cathepsin K was localized to the extracellular space surrounding developing chondrocytes in ML II zebrafish embryos, indicating a requirement for mannose 6-phosphate dependent lysosomal sorting. Here we link extracellular cathepsin K activity to abnormal bone and cartilage development in ML II animals by demonstrating that it disrupts the balance of TGF-beta-related signaling during chondrogenesis. TGFbeta signaling is elevated while BMP signaling is reduced in both feline and zebrafish ML II chondrocytes and osteoblasts, maintaining these cells in an immature state. Reducing cathepsin K activity or expression of the transcriptional regulator Sox9a in ML II zebrafish significantly improved the observed phenotypes. We further identify components of the large latent TGF-beta complex as novel targets of cathepsin K at neutral pH, providing a possible mechanism for enhanced TGF-beta activation in vivo. These findings highlight the complexity of the skeletal disease associated with MLII and bring new insight to the role of secreted cathepsin proteases in cartilage development and growth factor regulation. doi:10.1016/j.ymgme.2015.12.449
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292 Pregnancy in individuals with mucopolysaccharidosis (MPS): A case series Fiona Stewarta, Paul Harmatzb, Elizabeth Braunlinc, Andrew Bentleyd, Barbara Burtone, Nathalie Guffonf, Susan Haleg, Tracey Johnstonh, Susanne Kircheri, Pavan Kochharj, John Mitchellk, Ursula Plöckingerl, Zlatko Sisicm, aBelfast City Hospital, Belfast, United Kingdom, bUCSF Benioff Children's Hospital, Oakland, CA, United States, cUniversity of Minnesota, Minnesota, MN, United States, dUniversity Hospital of South Manchester NHS Foundation Trust, Manchester, United Kingdom, eLurie Children's Hospital, Chicago, IL, United States, fHopital Femme Mere Enfants, Lyon, France, gSeattle Children's Hospital, Seattle, WA, United States, hBirmingham Women's NHS Foundation Trust, Birmingham, United Kingdom, iInstitute of Medical Chemistry and Institute of Medical Genetics, Medical University of Vienna, Austria, jCentral Manchester University Hospitals, Manchester, United Kingdom, kMontreal Children's Hospital, Montreal, QC, Canada, lCharite-Universitatsmedizin, Berlin, Germany, mBioMarin Europe Limited, London, United Kingdom Due to an increase in life expectancy, a growing group of MPS patients are reaching adulthood and may have children. The outcomes of 9 pregnancies in 8 women (1 MPS IHS, 3 MPS IVA, 1 MPS IVB, 3 MPS VI) and from 4 men (2 MPS II, 2 MPS IVA) with MPS, followed up at 6 different tertiary care centers in the US, UK, France, Austria, and Germany are discussed. Seven of the women with MPS had complications during pregnancy, including lumbar pain, migraine, gastric pain and reflux requiring treatment, high relative weight gain, frequent spotting at 18 weeks, hospitalization for atrial tachycardia, medication adjustment due to hypotension, and hyperemesis gravidarum resulting in intermittent hypothyroidism. Most women stopped working during pregnancy. Only 2 women had uncomplicated and full-term spontaneous vaginal deliveries. Seven deliveries (in 6 women) were planned cesarean sections, mostly due to a disproportion in size between child and mother. Delivery at 37 weeks was required in one case because of maternal aortic stenosis, atrial tachycardia, and a history of nocturnal seizures. One woman required a blood transfusion at delivery. After delivery, 1 woman developed mastitis and a breast abscess requiring emergency surgery and an umbilical hernia requiring surgical repair; 1 woman had deterioration of cardiac problems. Neonatal intensive care was required in 2 cases. All 4 pregnancies and deliveries of the male patients’ partners were uncomplicated. All children had normal growth and development. Overall, this case series shows that women with MPS have high-risk pregnancies and deliveries. Nevertheless, with adequate evaluation of potential risks, proper counselling, planning and regular follow-up in a center with tertiary level maternal and neonatal care, the outcome of most pregnancies seems favorable. The cases were presented at an advisory board meeting sponsored by BioMarin Pharmaceutical Inc. doi:10.1016/j.ymgme.2015.12.450
293 Management of fertility and pregnancy in individuals with mucopolysaccharidosis (MPS) Fiona Stewarta, Paul Harmatzb, Elizabeth Braunlinc, Andrew Bentleyd, Barbara Burtone, Nathalie Guffonf, Susan Haleg, Tracey Johnstonh, Susanne Kircheri, Pavan Kochharj, John Mitchellk, Ursula Plöckingerl, Jennifer Semotokm, Zlatko Sisicn, aBelfast City Hospital, Belfast, United Kingdom, bUCSF Benioff Children's Hospital, Oakland, CA, United States, c University of Minnesota, Minnesota, MN, United States, dUniversity Hospital of South Manchester NHS Foundation Trust, Manchester,