40 Endocrine abnormalities in patients with mucopolysaccharidoses

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Abstracts / Molecular Genetics and Metabolism 92 (2007) S11–S34

enzyme activity. We have modified the published multiplex method for Pompe disease, Krabbe disease, Fabry disease, Gaucher disease and Niemann-Pick A/B to facilitate its transfer into newborn screening labs by optimizing the enzymatic reaction conditions, streamlining the sample preparation and clean-up procedures, and converting the assay to a high-throughput format. Data from the Taiwanese newborn screening pilot program and results of a feasibility study with the multiplex LSD enzyme assay will be presented. doi:10.1016/j.ymgme.2007.08.041

38 A proposed multicenter study of CNS structure and function in MPS I Elsa Shapiro a, Lawrence Charnas b, a University of Minnesota, Minneapolis, MN, USA, b Department of Pediatrics Background: Previous pilot research in patients with attenuated MPS I has suggested problems in declarative memory (encoding) and spatial functions, both hippocampal functions. In an ongoing pilot study, we are examining whether hippocampal structure and function is most affected in attenuated MPS I using both hippocampal volumes and diffusion tensor imaging as well as the CANTAB and conventional neuropsychological tests. Although the pathophysiology of the decline in untreated severe MPS I (Hurler syndrome) is unknown, animal studies and human pathology studies of children who died from transplant, find storage material in the hippocampus. The proposed multicenter study will (1) test the hypothesis that measures of hippocampal function and structure will be more impaired in patients with MPS I relative to normals and (2) develop accurate metrics for outcome studies of intrathecal enzyme treatment. We anticipate that encoding and declarative memory and spatial orientation will be more impaired than other neuropsychological functions (cognition, reading, attention, and executive function) in patients with attenuated MPS I. These findings will be correlated with results from volumetric studies (gray and white volumes, total hippocampus) and diffusion tensor imaging (afferent/efferent pathways). Methods: Subjects—50 fluent English speaking patients all with attenuated MPS I between ages 8 and 35 and on ERT; able to cooperate with both neuropsychological testing and unsedated MRIs. Neuropsychological measures includes brief IQ, memory, spatial, reading, and executive function tests in 5–10 regional centers. In 3–5 centers (5 if possible) volumetric measurements, diffusion tensor imaging (DTI), and the CANTAB will be done. Obstacles: DTI is not comparable unless scanner, software, and settings are identical. Based on surveys of collaborators, a 3 Tesla Siemens MRI scanner with identical software, settings, and protocols will be required for scanning centers. Realistically, 3–5 centers is the target due to instrument availability and quality control. The CANTAB will be done in these same centers. Next steps: (1) recruitment of co-investigators and centers that will be able to collect the aforementioned data distributed regionally across the US. (2) A multicenter proposal will be submitted to NIH. (3) Working out an equitable budget for administrative support, statistics, neuropsychological testing time and equipment, scanner time, and patient travel will be paramount. Implications: Need to better understand CNS pathology and develop metrics in order to measure the effectiveness of CNS treatment. doi:10.1016/j.ymgme.2007.08.043

39 Formation of a Lysosomal Disease Testing Network to enhance the delivery of diagnostic services to patients with lysosomal storage disorders Christine Eng a, J. Muenzer b, E. Wraith c, M. Beck d, R. Giugliani e, P. Harmatz f, A. Vellodi g, R. Martin h, U. Ramaswami i, M. Calikoglu b, S. Vijayaraghavan c, A. Puga e, B. Ulbrich i, M. Shinawi g, M. Cleary g, S. Wendt d, a Baylor College of Medicine, Houston, TX, USA, b University of North Carolina, Chapel Hill, NC, USA, c Royal Manchester Children’s Hospital, Manchester, UK, d Childrens Hospital University of Mainz, Mainz, Rhineland-Palatinat, Germany, e University of Cincinnati Medical Center, Cinncinati, OH, USA, f Children’s Hospital & Research Center Oakland, Oakland, CA, USA, g Stanford University School of Medicine,

Stanford, CA, USA, h Washington University School of Medicine, St. Louis, MO, USA, i Cambridge University Hospitals, Cambridge, UK The lysosomal storage diseases are a heterogeneous group of conditions that share several common features: (1) they are considered rare disorders in that they each affect far less than 200,000 individuals in the US, (2) recognition of characteristic disease manifestations by the medical community is frequently delayed, and (3) when recognized, confirmation or elimination of a suspected diagnosis may be compromised by difficulty in accessing specific diagnostic services. The objective of this proposal is to form a cooperative Lysosomal Disease Testing Network that will address the needs of the constituencies that comprise the Lysosomal Disease Network—the patients and families, clinicians, diagnostic lab scientists, and basic researchers—with regard to diagnostic services. Most importantly, it will facilitate access to diagnostic testing services for the families affected by lysosomal disorders. It will also serve as a resource for physicians, genetic counselors, and other medical professionals as they seek laboratories to perform indicated testing. It will identify those disorders for which testing services are limited, and create a mechanism to address these deficiencies among the network laboratories. Finally, it will create bridges between basic researchers and diagnostic lab scientists as they seek to translate research findings, particularly new disease tests, to CLIA certified diagnostic labs. The model of diagnostic labs partnering with research labs and clinicians will also enhance clinical research efforts, such as genotype phenotype correlations. As gaps in coverage of disease testing are identified or as new disease tests become feasible, a plan will be implemented to encourage the development of these tests by at least one CLIA certified network laboratory. A long term goal would be to encourage a model in which testing is offered in at least two labs, in order to provide a choice to patients and physicians, as well as to allow for future quality assurance sample sharing. An additional goal would be to ensure that, when feasible, testing for specific disorders is available by both biochemical and molecular diagnostic methods. The Lysosomal Disease Testing Network will be a major resource for all members of our organization. While its main goal is to ensure that clinical testing is available for all LSDs, the lab network will also provide an infrastructure for future collaborations within the Lysosomal Disease Network. doi:10.1016/j.ymgme.2007.08.044

40 Endocrine abnormalities in patients with mucopolysaccharidoses Lynda Polgreen a, Melissa Plog b, Paul Orchard a, Bradley Miller a, Anna Petryk a, Chester B. Whitley a, a Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA, b Medical School, University of Minnesota, Minneapolis, MN, USA Background: Little is currently known about endocrinologic complications due to mucopolysaccharidoses (MPS). Short stature is common in patients with MPS, even after enzyme replacement therapy (ERT) or hematopoietic stem cell transplantation (HSCT), and is likely secondary to a combination of structural, metabolic, and endocrine abnormalities. At this time, to our knowledge, no systematic assessment of endocrine function has been completed in patients with MPS. Because of the persistent short stature and histologic evidence of accumulation of glycosaminoglycans in endocrine glands, we hypothesize that children with MPS have an increased prevalence of growth hormone deficiency, hypothyroidism, and delayed or precocious puberty, as well as adrenal insufficiency, and that for the post-HSCT patients this prevalence is beyond that already associated with HSCT. Methods: To address the question why children with MPS have short stature, we began with a retrospective chart review of 66 patients with Hurler syndrome (28 females, 38 males) who received a HSCT at the University of Minnesota between 1985 and 2005. In addition, we began prospectively screening for endocrinopathies in children with MPS prior to and following ERT and HSCT.

Abstracts / Molecular Genetics and Metabolism 92 (2007) S11–S34 Results: Of the 48 patients included in the growth evaluation, 70.8% (n = 34) had a height < 2 SD at the most recent evaluation. In the total cohort of 66 patients with Hurler syndrome, 9% (n = 6) were growth hormone deficient by stimulation testing (10 tested), 12% (n = 8) had IGF-1 levels < 2 SD (16 tested), and 32% (n = 21) had hypothyroidism (59 tested). Of all females <8 years and males <9 years, 8.7% (n = 4 of 46) had precocious puberty. Of all females >13 years and males >14 years, 12.5% (n = 1 of 8) had delayed puberty. The first two patients with Hunter syndrome screened for endocrinopathies had IGF-1 deficiency (< 2 SD), and one had adrenal insufficiency (peak stimulated cortisol of 17.1 mcg/ dL). Conclusions: Preliminary data suggest that children with Hurler syndrome after HSCT are at increased risk for growth hormone deficiency, hypothyroidism, premature or delayed puberty, and children with Hunter syndrome may be at increased risk for IGF-1 and adrenal insufficiency before ERT. More data are needed to confirm these preliminary findings in both the HSCT and ERT populations and to discriminate between the effect of HSCT and the disease itself. Until this data is available, we recommend systematic screening for endocrine causes of short stature, as well as adrenal function testing, in patients with Hurler and Hunter syndrome before HSCT or ERT, and then annually. This will allow earlier detection, minimize complications due to undiagnosed disease, and possibly improve adult height. doi:10.1016/j.ymgme.2007.08.045

41 Preparing for experimental therapeutics in JNCL Jonathan Mink, University of Rochester Medical Center, Rochester, NY, USA doi:10.1016/j.ymgme.2007.08.046

42 Pathogenesis of juvenile Batten disease David A. Pearce, University of Rochester School of Medicine, Rochester, NY, USA

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43 Neurobehavioral function in Batten disease Heather Adams a, E.A. deBlieck b, J.M. Kwon b, F.J. Marshall b, L.S. Dure b, P.G. Rothberg c, R.C. Jordan d, D.A. Pearce e, a University of Rochester School of Medicine & Dentistry, Rochester, NY, USA, b Department of Neurology, University of Alabama, Birmingham, AL, USA, c Department of Genetics, Williams College, Williamstown, MA, USA, d Williams College, Williamstown, MA, USA, e Center for Aging and Developmental Biology, University of Rochester School of Medicine, Rochester, NY, USA Introduction: Juvenile Neuronal Ceroid Lipofuscinosis (JNCL; eponym: Batten disease) is a childhood neurodegenerative disorder of childhood. Core symptoms include vision loss, seizures, and cognitive-motor decline impact child functioning and caregiver burden. Neurobehavioral symptoms are prominent but not well understood. Hypothesis: Neurobehavioral assessment can provide reliable and valid assessment of JNCL. Methods: Neurobehavioral assessment has been conducted in over 40 children with JNCL. This has included both cross sectional and longitudinal studies of neuropsychological function and longitudinal assessment of behavioral and adaptive functioning skills. We have examined mean scores at each time point and change in neurobehavioral function scores over successive evaluations. We have also examined correlations among neurobehavioral function, genotype, seizure history, and disease duration. Results: Subjects were significantly impaired on tests of attention, memory, verbal IQ, and verbal fluency. Impairments were correlated with disease duration, motor function, and seizure history. Longer symptom duration at first assessment was associated with reduced functional skills. Preliminary analysis of subjects completing annual re-evaluation suggest declines in working memory and functional skills over time. Neurobehavioral assessments correlated well with clinician ratings of behavior and psychiatric function on a neurologic rating scale (Unified Batten Disease Rating Scale). Conclusions: Neurobehavioral deficits are pervasive and progressive. Future research will focus on clarifying the relationship among disease duration, motor function, and neuropsychological performances, including the relative sensitivity of neuropsychological testing at different stages of motor impairment or disease duration. doi:10.1016/j.ymgme.2007.08.048

Juvenile neuronal ceroid lipofuscinosis (JNCL) is an autosomal recessive disorder of childhood caused by mutations in CLN3. The onset of the disease typically occurs around 4–7 years of age with progressive visual loss that culminates in total blindness. The disease progresses to include seizures, memory loss, and motor deficits followed by premature death before or around the third decade of life. Using a Cln3 loss of function (Cln3 / ) mouse we have tracked the time course of neurological disease and have discovered alterations at the cellular, molecular and biochemical level that underlie the progressive loss of vision and deteriorating motor function. Motor deterioration in JNCL can include decreased coordination, gait abnormalities, myoclonic jerks, an inability to initiate movements, and spasticity. First, focusing on the cerebellar motor system of the Cln3 mouse, we demonstrate coordination deficits that are in part, due to alterations in cerebellar cellular architecture. Further exploring deficits in movement associated with JNCL, we examined the striatal motor system. Later in Cln3 / mouse pathology we demonstrate an imbalance in the catabolism of dopamine, specifically within the striatum, that leads to oxidative damage, decreased post-synaptic D1_ receptors, inflammatory changes, and cell loss in CNS regions that form connections with the striatum. Finally, a more detailed examination of an autoimmune component to the disease which may be contributing to the described motor dysfunction has revealed a targeted approach to ameliorating this progressive aspect of the disease. doi:10.1016/j.ymgme.2007.08.047

45 Mouse models of Gaucher disease: Insights into visceral and CNS disease progression Greg Grabowski, USA doi:10.1016/j.ymgme.2007.08.050

46 A perspective on treatment and cures of Gaucher disease John Barranger, University of Pittsburgh, Pittsburgh, Pennsylvania, USA Gaucher disease (GD) was the first lysosomal storage disorder to be treated with enzyme replacement therapy (ERT). This advance was a consequence of the identification and use of a lectin based, naturally occurring enzyme protein (drug) delivery system utilizing mannose residues in the oligosaccharide side chains of glucocerebrosidase (GC). After 15 years of experience, data from the ICGG (Gaucher Registry) confirms clinical impressions of excellent responses of patients to the therapy and its safety as well as dose responsive improvements in hemoglobin, thrombocytopenia, splenomegaly, bone pain (1) and bone mineral density (2). ERT is the standard of care for GD which can alleviate all of the symptoms of the disease or prevent them, if instituted early in the course of patients with type 1 disease. New approaches to therapy of GD include substrate reduction therapy (SRT) (3) and enzyme enhancement therapy (EET) frequently referred to as chaperones (4). SRT seeks to reduce the burden of glucocerebroside (GL1) on the degradative pathway. Inhibition of glycoslyceramide