glycoproteinosis patient cohort - to whom should we target education

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Abstracts

dogs less than 6 months of age were performed to identify molecular pathways active in early fucosidosis pathophysiology. These included gene expression profiling of the frontal cortex, characterization of neuroinflammation and oligodendrocyte and myelin abnormalities in the central nervous system and examination of cytokine expression in the cerebrospinal fluid (CSF). From this it was identified that cytokine (CCR1, CCR5) and cathepsin (CTSC, CTSD, CTSS) genes contributing to neuroinflammation and apoptotic processes were upregulated in preclinical fucosidosis frontal cortex and myelin genes (CNP, MAG, MAL and OPALIN) were downregulated (p b 0.05). Follow up investigations identified oligodendrocyte vacuolation by 5 weeks of age, and 67% reduction (p b 0.001) of mature oligodendrocytes in the corpus callosum, consistent with hypomyelination. MCP-1/CCL2 and KC/CXCL1 were chemokines that demonstrated significant (p b 0.001) and rapid elevations in CSF over a 2 month period from 8 weeks to 16 weeks in affected dogs compared to controls, and may have potential as biomarkers. Overall, the results of these studies provide a framework for a model of fucosidosis pathogenesis where the accumulation of fucosylated substrates within neurons and glia during the first 6 months of life, results in the loss of oligodendrocytes and an inflammatory response which primes neurons and glia for apoptotic death, resulting in clinical signs.

doi:10.1016/j.ymgme.2013.12.087

76 Recombinant human β-glucuronidase enzyme replacement therapy for mucopolysaccharidosis type VII: report of the first patient treated Joyce E. Foxa, Emil D. Kakkisb, William S. Slyc, aSteven and Alexandra Cohen Children’s Medical Center, New York, NY, USA, bUltragenyx Pharmaceutical Inc, Novato, CA, USA, cSt. Louis University School of Medicine, St. Louis, MO, USA Mucopolysaccharidosis type VII (MPS VII, Sly syndrome), is a very rare lysosomal disease, caused by deficiency of beta-glucuronidase (GUS), required for the degradation of dermatan sulfate and heparan sulfate. Clinically, this multi-systemic disorder resembles MPS I and MPS II, however marked heterogeneity of presentation and progression has been noted. Two decades of animal research demonstrate effective treatment with enzyme replacement therapy (ERT) in MPS VII mouse models. Furthermore, there are extensive data on approved ERT in three other MPS disorders. However, there is no product approved for treatment of MPS VII patients. We present the clinical features of the first patient with MPS VII who was recently infused with recombinant human GUS (rhGUS) as ERT. The patient is an 12 year old boy diagnosed with MPS VII by fibroblast assay, consistent with the clinical features including hydrops fetalis, hepatosplenomegaly, heart valve disease, frequent sinopulmonary infections and upper airway obstruction, declining pulmonary function, dysostosis multiplex, and spinal cord compression requiring cervical fusion. His urinary glycosaminoglycan levels were significantly elevated, at N4x the upper limit of normal, at baseline. Despite a tracheostomy, nocturnal CPAP and oxygen therapy, significant pulmonary restriction and obstruction led to oxygen dependence, rising CO2 levels in the 60-80 range, approaching respiratory failure and the need for full-time ventilation. Since no additional medical measures could improve his function, we implemented experimental ERT by infusing rhGUS at 2 mg/kg over 4 hours every 2 weeks, after pretreatment with an oral antihistamine. To evaluate his response to therapy, urinary GAG levels, pulmonary function, oxygen dependence, CO2 levels, cardiac valve function, liver and spleen size, and growth velocity will be assessed. Safety will be evaluated by standard assessments and observance of any

infusion-related reactions. Data on efficacy and safety in this first report of ERT in MPS VII will be reported. doi:10.1016/j.ymgme.2013.12.088

77 Correction of broad molecular impairments in a mouse model of MPS IIIA by systemic rAAVrh74-hSGSH gene delivery Haiyan Fu, F. Jason Duncan, Bartholomew Naughton, Kimberly Zaraspe, Darren Murrey, Tierra Ware, Aaron Meadows, Douglas M. McCarty, Research Institute at Nationwide Children's Hospital, Columbus, OH, USA Mucopolysaccharidosis (MPS) IIIA is a neuropathic lysosomal disease caused by deficiency in N-sulfoglucosamine sulfohydrolase (SGSH). A genome-wide gene expression array in MPS IIIA mice showed broad molecular abnormalities with significant dysregulation (≥2 fold) of numerous genes in the brain (516 genes) and peripheral blood white cells (PBWC) (632 genes), of which 111 genes were significantly altered in both the brain and PBWC. To target the root cause of MPS IIIA, we used a trans-BBB neurotropic rAAVrh74 vector to deliver the human SGSH gene into 4-6-wk-old MPS IIIA mice by an intravenous injection. The treatment resulted in global CNS and widespread somatic restoration of SGSH activity, clearance of GAG storage, improved behavior, and significantly extended survival in these animals. The rAAVrh74-hSGSH treatment also led to correction of the majority of the transcriptional abnormalities in the brain (489/516, 94.8%) and PBWC (607/632, 96%). Importantly, transcripts from 400 and 453 genes were normalized in the brain and PBWCs, respectively. These results demonstrate that efficient restoration of SGSH activity can result in a complete, or near complete correction of MPS IIIA cytopathology. Our data also demonstrate that blood transcriptional profiles may reflect the biopathological status of MPS IIIA, and also respond to effective treatments, offering a minimally invasive set of specific biomarkers for disease progression and therapeutic assessments.

doi:10.1016/j.ymgme.2013.12.089

78 Early clinical features and time to diagnosis in a Scottish mucopolysaccharidosis/glycoproteinosis patient cohort - to whom should we target education Peter J. Galloway, Alison Kelly, Janet Gardner-Medwin, Bernd Schwahn, Yorkhill Children's Hospital, Glasgow, UK There is often a delay in establishing a diagnosis of mucopolysaccharidosis (MPS) or a related disorder after the appearance of clinical signs. With effective treatments available, there is benefit to early diagnosis in the majority of cases. Yorkhill Children’s Hospital in Glasgow provides a specialist metabolic service and is a referral centre for haemopoeitic stem cell transplantation for Scotland. Earlier identification of children with clinical features suggestive of storage disorders would allow for accelerated testing and treatment. Our goal was to establish the time from first hospital review to diagnosis of local cases of MPS and related disorders, and identify common presenting features. Case records for 19 children treated at Yorkhill hospital were reviewed (9 MPS I- severe, 2 MPS Iattenuated, 2 MPS II, 4 MPS IVA, 1 Multiple Sulphatase Deficiency and 1 Alpha Mannosidosis). Information collected included: age at

Abstracts

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diagnosis; symptoms/signs present on first referral to hospital and at diagnosis; time between first referral and diagnosis; specialties consulted for symptoms/signs attributable to storage disorder before diagnosis was made; specialty making the diagnosis and treatment received. Median age of all cases at diagnosis was 16 months (range 9.5 months-15 yrs 3 months). Time to diagnosis ranged from 0 months (prenatal diagnosis) to 11 years (alpha mannosidosis). Median time to diagnosis in severe MPS I was 9 months. All cases of MPS II and MPS I (attenuated form) had a time to diagnosis exceeding 3 years 10 months. Most diagnoses were made by a specialist metabolic team (10/19 cases). The most frequent presenting features were hernia (6/19 cases), lumbar kyphosis (5/19 cases) and hearing loss (3/19 cases) Delay to diagnosis was common, echoing data from international MPS registries. Knowledge of common presenting features will allow for targeted education to aid early recognition of children with MPS particularly to rheumatology and orthopaedics.

modes of expression (agitation, screaming, crying) and passive modes (no communication, withdrawal, lack of facial expression). Passive signs were often mentioned in cases of deep psychological distress. The meanings given to these signs were: fear, anxiety, distress, sadness, depression, stress, anger and frustration. Responses included socializing; providing comfort and references; meeting basic needs; administering medication. Antidepressant drugs were prescribed for two purposes: either for an anticonvulsive-antidepressant effect, or after painkillers had proven ineffective. Three contexts that may promote psychological distress were identified: epilepsy, pain and disease progression. More extensive research will permit us to carry out the quantitative analysis needed to test the relevance of each of these three contexts and to evaluate the prescription of antidepressants.

doi:10.1016/j.ymgme.2013.12.090

80 Tissue-specific X chromosome inactivation studies as a decisionmaking criteria for enzyme replacement therapy in female heterozygotes for Fabry disease

79 Psychological distress in children when lysosomal disease impairs communication: what parents and professionals report Delphine Genevaza, Alessia Perifanoa, Régine Scellesb, aVaincre les Maladies Lysosomales Organisation (VML), Massy, France, bRouen University, Rouen, France During discussions with families participating in “Vaincre les Maladies Lysosomales” (VML, the French non-profit organisation of patients and their families), it is regularly reported that children with lysosomal disease experience periods of depression. When these periods of depression are reported to physicians, they are usually diagnosed as progression of the disease and not as a psychological problem. Paradoxically, during the past few years, there has been an increase in antidepressant prescriptions for these children. In most cases, lysosomal diseases lead to severe disabilities, with large variability in the type and the severity of lesions including cognitive impairments. For children whose ability to communicate has been damaged, how can psychological suffering be identified, in distinction from physical pain? How is it expressed? VML therefore decided to conduct preliminary research to identify the signs of possible mental suffering. Methodologically, this study required access to the subjective experience of these children despite their communication difficulties. Recent studies on the care of children with multiple disabilities (San Salavadour 2000; Scelles 2003; Camelio 2006; Pautrel, 2009) have used the children’s entourage to access their feelings. The entourage is considered to be a translator of the child’s feelings because it understands his or her non-verbal language (Camelio, 2006). Using this methodology, four parents and four professionals were interviewed in semi-structured interviews which were subjected to a qualitative analysis. The purpose of this research was to identify signs of potential psychological suffering and the meaning attributed to these signs by the entourage. Each sign was explored across different dimensions: the context in which the sign is expressed, the meaning attributed to it by the entourage and the value which they considered it to have (correctly or incorrectly), and finally the entourage’s response to the child and how it evaluated the relevance of the response (appropriate or inappropriate). This exploration of signs allowed us to consider the entourage’s interpretations and to evaluate the relevance of their interpretations. In this way we also allowed for possibility of projections, doubts and errors of interpretation on the part of the entourage. Thirteen children were involved, and twelve of them were described as having shown signs of psychological distress. Six lysosomal diseases were represented. The signs which were mentioned included both active

doi:10.1016/j.ymgme.2013.12.091

Dominique P. Germain, Lucia Echevarria, University of Versailles, Montigny, France Background: Fabry disease is an X-linked disorder caused by the deficient activity of lysosomal α-galactosidase A. Although historically described as ‘asymptomatic carriers’, heterozygotes can develop a wide range of clinical signs and symptoms. The wide clinical spectrum has been attributed to X chromosome inactivation (XCI), although this hypothesis remains controversial. Aim: To evaluate the importance of XCI in the clinical phenotype of heterozygotes and its potential interest in deciding for eligibility for enzyme replacement, considering for the first time intraindividual tissular differences of XCI. Methods: Forty-one heterozygous females were enrolled in the study. Exhaustive renal, cardiac and central nervous system work-up, together with 2 global severity score indexes (MSSI and DS3) were used to assess the clinical phenotype. The methylation status of X chromosome was studied in 4 different tissues. Results: Differences in XCI patterns existed between tissues. Twenty-eight heterozygotes were found to be randomly inactivated in at least 3 tissues, 13 patients had two or more tissues with skewed inactivation. An age-dependant worsening of clinical severity scores, cardiac mass and renal function was found in randomly inactivated patients, consistent with progressive accumulation of Gb3. In contrast, no age correlation could be found in patients with skewed inactivation, whose clinical phenotype was attenuated when the wild-type GLA allele was predominantly expressed. Residual enzyme activities correlated with inactivation profiles. Discussion: XCI appears as a prognostic factor of Fabry disease progression in heterozygotes. We proposed XCI to be integrated in the decision-making criteria of eligibility for enzyme replacement in this subset of patients. doi:10.1016/j.ymgme.2013.12.092

81 Living in the light of rare and orphan diseases Levi G. Gershkowitz, Independent (photographer and researcher), Baltimore, MD, USA