An examination of the current metabolic education curriculum across genetic counseling training programs in the United States and Canada

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children primarily aged 1-5 years at baseline and to correlate changes in clinical features of the disease, in particular changes in DQ, with both MRI characteristics and biochemical markers of disease burden. Concurrently, a treatment study (BMN 250-201) is also planned using BMN 250. Part 1 of this treatment study is a doseescalation period to establish safety; Part 2 is a dose-expansion period and consists of patients rolling over from the 250-901 observational study. Efficacy will be assessed by comparing changes in disease progression in the observational study versus changes observed in Part 2 of the treatment study. doi:10.1016/j.ymgme.2015.12.438

281 Sortilin expression and uptake of α-galactosidase A: A general mechanism of endocytosis in Fabry disease cell types Jin-Song Shena, Taniqua S. Daya, Xing-Li Menga, Zhi-Ping Liub, Raphael Schiffmanna, aBaylor Research Institute, Dallas, TX, United States, b University of Texas Southwestern Medical Center, Dallas, TX, United States Enzyme replacement therapy (ERT) is the main specific therapy for Fabry disease; however, its clinical effect is incomplete. A better understanding of the mechanism of enzyme uptake is crucial to develop more effective ERT. It was generally believed that mannose-6phosphophate receptor (M6PR)-mediated endocytosis is a key mechanism in ERT for Fabry disease. However, our recent study with nonphosphorylated α-galactosidase A (α-gal) demonstrated the importance of mannose receptor and other non-M6PR-mediated pathways in delivery of α-gal. Recently, sortilin was reported to mediate uptake of α-gal in cultured podocytes and glomerular endothelial cells. However, the function of sortilin as α-gal receptor has not been fully established, and it was not tested in Fabry disease cells. Also, it remains unclear whether this endocytic pathway is kidney cell-specific or has general implication to other cell types. We found sortilin to be expressed in all the cell types tested; these include cultured micro- and macrovascular endothelial cells, cardiomyocytes, renal tubular cells, macrophages, and fibroblasts. The role of sortilin in α-gal uptake was studied in micro- and macrovascular endothelial cells, and fibroblasts obtained from human or mouse with α-gal deficiency. Uptake was evaluated by intracellular α-gal activities and protein levels. Binding/uptake of α-gal in these cell types was inhibited by neurotensin, a competitive ligand of sortilin, and/or receptor-associated protein that universally blocks uptake of ligands by LDL receptor family and sortilin. The function of sortilin was further determined by RNA interference. Downregulated sortilin expression was associated with decreased α-gal uptake in these cells. These results suggest that sortilin contributes to binding and internalization of α-gal in Fabry disease cells, and that this mechanism exists in a broad range of cell types. Endocytosis of α-gal involves a combination of multiple receptors; manipulation of these receptors may be a strategy to improve enzyme delivery to hard-to-reach cell types.

and neurodegeneration are important components of the central nervous system (CNS) phenotype. Pentosan polysulfate (PPS) is an FDA/EMA approved drug that has potent anti-inflammatory properties. We have previously demonstrated its efficacy in animal models of MPS VI and I, particularly in the skeletal and cardiac phentoypes (Simonaro et al., 2013; Frohbergh et al., 2014; Simonaro et al., in preparation). In addition to reducing inflammation, PPS treatment substantially reduced glycosaminoglycan (GAG) storage in urine and tissues. It is not currently known whether systemically administered PPS crosses the blood brain barrier (BBB), although dogs with MPS I treated for 12 months with biweekly subcutaneous (SQ) PPS exhibited signficant reduction of cytokines in their cerebrospinal fluid. The current study was designed to evaluate the impact of SQ PPS on neuroinflammation, neurodegeneration and neurobehavioral defects in MPS IIIA mice. PPS was administered once weekly (25 and 50 mg/kg) beginning at one week of age. Reduced inflammation was observed, including in the brains of the treated MPS IIIA mice. Currrent analysis is focused on evaluating other CNS endpoints, including neural cell death, expression of pathogenic neural proteins (e.g., Tau, β-amyloid), and reduction of heparan sulfate storage in the brain. Effects of PPS on other MPS IIIA mouse organ systems also will be documented. doi:10.1016/j.ymgme.2015.12.440

283 Two cases with mucopolysaccharidosis type VII Serap Sivri, Emine Pektas, Yilmaz Yildiz, Ali Dursun, Aysegul Tokatli, Turgay Coskun, Hacettepe University, Ankara, Turkey Mucopolysaccharidosis type VII (MPS VII) is caused by deficiency of beta-glucuronidase. We present two female patients with this rare disorder. Patient A was hospitalized postnatally due to edema and pericardial effusion detected by prenatal ultrasonography. She had coarse facies and a short neck. Peripheral smear showed granular leukocytes. Urinary glycosaminoglycans were high and leukocyte betaglucuronidase activity was low, establishing the diagnosis of MPS VII. She was lost to follow-up until referral to an orthopedics clinic with walking difficulties 10 years later. She had tonsillar hypertrophy, hearing loss, shallow acetabulae, valvular insufficiencies and mild intellectual disability. She was recently enrolled in an enzyme replacement therapy trial. Patient B presented to the gastroenterology department at 2 months of age with jaundice and hepatosplenomegaly. Bone marrow examination revealed granulated cells. Liver biopsy showed intracellular cholestasis. She was lost to follow-up until she was 8 years old, complaining of limited neck movements. She now had coarse facies. Urine glycosaminoglycan electrophoresis suggested MPS VII, confirmed by profoundly low beta-glucuronidase activity. She is now 22 years old, has kyphoscoliosis, hepatomegaly, valvular insufficiencies and mild intellectual disability. MPS VII patients usually exhibit milder phenotypes than other types of MPS. These cases underline the possibility of MPS VII in the differential diagnosis of various systemic findings.

doi:10.1016/j.ymgme.2015.12.439 doi:10.1016/j.ymgme.2015.12.441 282 Pentosan polysulfate and neuroinflammation in mice with mucopolysaccharidosis type IIIA mice Calogera M. Simonaro, Ningning Guo, Edward H. Schuchman, Icahn School of Medicine at Mount Sinai, NY, NY, United States Studies in murine models of Sanfilippo syndrome (mucopolysaccharidosis type III; MPS III) have revealed that neuroinflammation

284 An examination of the current metabolic education curriculum across genetic counseling training programs in the United States and Canada Elizabeth Smitha, Catherine Walsh Vockleyb, aEmory University, Decatur, GA, United States, bChildren’s Hospital of Pittsburgh/UPMC, Pittsburgh, PA, United States

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In 2014, the National Society of Genetic Counselors completed their biennial Professional Status Survey aimed at offering an accurate reflection of the genetic counseling profession. A total of 1,624 genetic counselors self-reported their primary specialty in this survey. Only 1.4% of clinical genetic counselors and 3.3 % of non-clinical genetic counselors reported a specialty of metabolism and lysosomal diseases (LD). It has been well established that genetic counselors are vital to the practice of metabolic genetics and LD in the traditional clinical setting. Genetic counselors have had an increasing presence in non-clinical settings such as newborn screening, support groups, and industry. Given the broad spectrum of applications of genetic counseling skills in the provision of care for patients with metabolic disorders and LD, it is essential that genetic counseling students have the didactic training as well as the practical exposure to professional opportunities in this field. The purpose of this project was to document graduate school exposure to metabolic disorders and LD for genetic counseling students and to identify potential barriers these students may encounter during their training that may deter them from entering these fields. Program directors representing 33 accredited genetic counseling programs were surveyed. Preliminary results indicate the majority of genetic counseling programs provide intensive didactic training in metabolic disorders and LD to their students. A common theme among many survey respondents, however, suggested genetic counseling students may not have access to the practical application of their didactic training in the clinical setting and are not exposed to the non-clinical areas of practice. Results from this preliminary study will be used to develop a survey for genetic counseling students and recent graduates on their perspectives about the topic, and ultimately to define program and student needs so that gaps in educational resources can be addressed.

number of moderately affected Farber patients than previously thought, many of whom may have been misdiagnosed with juvenile idiopathic arthritis. A natural history study is planned to establish a better understanding of how gene mutations, biochemical, immunologic and clinical phenotypes are associated in acid ceramidase deficiency, to assess the treatments employed until now, and to prospectively follow changes over time. This is particularly important because enzyme replacement therapy is expected to enter clinical trials for Farber disease in 2016. Since May 2014, 24 nonstem cell transplanted and 13 transplanted patients have been added to the Farber cohort. The information gathered from these patients to date reinforces the validity of the characteristic symptoms of Farber disease: early-onset polyarticular arthritis, subcutaneous nodules and dysphonia. However, it also reveals that there are patients who present with only one or two of these symptoms, that there is a varied response to intensive anti-inflammatory treatment or haematopoetic stem-cell transplant, and that there are patients whose phenotype is so mild that they have few physical signs of disease and little impairment of everyday function. We present here clinical characteristics, along with genetic and biochemical data on a large cohort of 17 non-transplanted patients with Farber disease.

doi:10.1016/j.ymgme.2015.12.442

Archana Soni-Jaiswala, Jane Robertsa, Simon A. Jonesa, Iain A. Brucea, Peter Calleryb, aCentral Manchester Teaching Hospitals NHS Trust, Manchester, United Kingdom, bUniversity of Manchester, Manchester, United Kingdom

285 Farber disease is characterized by typical features but a broad phenotypic spectrum: Selected information from a cohort of 37 patients Alexander Solyoma, John Mitchellb, Karoline Ehlertc, Pranoot Tanpaiboond, Bo Magnussone, Giedre Grigelionienee, Boris Hüglef, Norberto Guelbertg, Nur Arslanh, Balahan Makayh, Seza Ozeni, Ezgi Deniz Batui, Laila Selimj, Zahra Hadipourk, Fatemeh Hadipourk, Alejandra Cuevas-Cidl, Ratna Purim, Calogera Simonaron, Xingxuan Hen, Edward Schuchmann, aPlexcera Therapeutics LLC, New York, NY, United States, bMontreal Children's Hospital, Montreal, QC, Canada, c University Medical Center Greifswald, Greifswald, Germany, dChildren's National Medical Center, Washington, DC, United States, eKarolinska University Hospital, Stockholm, Sweden, fGerman Center for Pediatric and Adolescent Rheumatology, Garmisch-Partenkirchen, Germany, gChildren's Hospital of Cordoba, Cordoba, Argentina, hDokuz Eylul University, Izmir, Turkey, iHacettepe University Faculty of Medicine, Ankara, Turkey, jCairo University Children's Hospital, Cairo, Egypt, kSarem Cell Research Center and Hospital, Tehran, Islamic Republic of Iran, lSouth Stockholm General Hospital, Stockholm, Sweden, mSir Ganga Ram Hospital, New Delhi, India, n Mt. Sinai School of Medicine, New York, NY, United States Mutations in the ASAH1 gene result in the deficient activity of acid ceramidase, leading to the accumulation of the lipid ceramide and the development of two distinct disease phenotypes: Farber disease and Spinal Muscular Atrophy with Progressive Myoclonic Epilepsy (SMA-PME). Farber disease represents a broad spectrum of severity presenting from infancy through childhood, primarily reflecting the pro-inflammatory and pro-apoptotic characteristics of ceramide. In collecting initial information from the largest cohort of Farber patients to date, we have found that there is likely a greater

doi:10.1016/j.ymgme.2015.12.443

286 Attenuated mucopolysaccharidosis II; Parental beliefs about the impact of disease on the quality of life of their children

The availability of enzyme replacement therapy, alongside improved multi-disciplinary management, has transformed MPS II from a lifelimiting illness into a chronic illness with improved functional outcomes. Despite the improvements they continue to carry a burden of disease, including head and neck disease, into adulthood. This exploratory qualitative study explores the impact of this disease on the quality of life of the children with the attenuated variant of MPS II and their families. 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 interviewed were coded and emergent themes explored until saturation occurred. Six families were interviewed. Interpretive analysis revealed that for the parents of children under the age of three, hearing loss was the predominant worry. As the children reached primary school age (5-6 yrs), the main concern was delayed acquisition of language. Towards the end of primary school (10-11 yrs) the focus had shifted towards the child’s mental capacity and their mild developmental delay. The parents of adolescents (11-16) were focused on preventing social isolation in their child and assisting them in achieving life skills that would promote independent living in the future. We found overall that in the formative years, they wanted their child to integrate into broader society, achieving the same milestones as normal children in mainstream school, whilst in the latter years, the focus shifted and they were more accepting of their child’s differences and wanted them to be surrounded by a peer group, with similar needs, allowing their child to feel less ‘different’. There was an evolution with time of the issues important to parents and by proxy, their children with desire for their children to ‘fit-in’ and integrate with their peers, at the heart of this. doi:10.1016/j.ymgme.2015.12.444