19. An unusual case of Pompe disease presenting as muscular dystrophy

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Abstracts / Molecular Genetics and Metabolism 93 (2008) S14–S46

16. Serum biomarkers and clinical effect of off-label use of miglustat in GM1 gangliosidosis Lawrence Charnas, University of Minnesota, Minneapolis, MN, USA Background: GM1 gangliosidosis, a deficiency in beta-galactosidase with storage of gangliosides causes skeletal, neurologic and other organ dysfunction. Glucocerebroside synthesis inhibition by miglustat might decrease GM1 accumulation and offer clinical benefit. Study Design: Observational clinical experience Patient Descriptions: Three patients (1 infatntile, 2 juvenile onset) with GM1 gangliosidosis were treated with miglustat. Patient 2, Outcomes: Dosage ranged from 5 to 15 mg/kg/day in divided doses titrated to tolerability. Side effects included weight loss in the two juvenile onset patients without diarrhea. Chitotriosidase (CHITO) levels, angiotensin converting enzyme (ACE) and tartrate resistant acid phosphatase (TRAP) measures were markedly elevated in the infant. No follow up studies were available. The infantile patient was treated from 7 to 19 months, and died at 23 months of age. ACE levels were consistently normal in both juvenile patients. TRAP levels were consistently in the 11-year-old patient during treatment. After 12 months of therapy, she showed marked progression of neurologic disease and elevation of CHITO with normalization of CHITO but not TRAP after stopping miglustat. Patient 3 showed consistently elevated CHITO levels without response to miglustat and no clinical change. Conclusions: Miglustat at the prescribed doses produced no demonstrable clinical benefit in 3 patients. Serum biomarkers of macrophage activation are variable across disease forms, but do not appear to respond in juvenile patients.

can be difficult both logistically and from a patient/caregiver perspective. If handled incorrectly, anxiety and uncertainty can sabotage a successful transition. Preparing the patient mentally for the change is the first step to success. Discussing the rationale for the change and involving the patient in the move allows a sense of autonomy by providing active participation in their therapy. We begin discussion regarding the change, months in advance to assure patient comfort. An introductory visit to the new facility and provision of educational sessions, allows the new team an opportunity to actively participate in the patient care plan. Educational sessions provide an opportunity for active participation of caregivers and encourages a sense of ownership to the plan and the patient. Attending the first infusion adds comfort to the new team and the patient who will undoubtedly experience anxiety in a new setting. For home infusions, it is important to have the community nurse visit the patient in the hospital setting during an infusion for introductions in a familiar environment. Using a stepwise approach by first involving the patient and then bringing in the other parties allows time for the transitional process to evolve. Provision of educational sessions and attending the first infusion allows a smooth handover of care. This approach may seem time consuming; however, the effort is worth it when both patient and new care givers embrace the transition. doi:10.1016/j.ymgme.2007.10.030

doi:10.1016/j.ymgme.2007.10.028

19. An unusual case of Pompe disease presenting as muscular dystrophy Kristina Cusmano-Ozog, Hannes Vogel, Tina Cowan, Gregory Enns, Stanford University, Stanford, CA, USA

17. Immunosuppression as a novel therapeutic target in Batten disease? Jonathan Cooper a, Julian Castaneda b, Andrew Wong a, Michael Horak a, Sabrina Seehafer b, Jared Benedict b, Jill Weimer b, Timothy Curran b, Ming Lim a, David Pearce b, a Institute of Psychiatry, King’s College London, London, London, UK, b University of Rochester Medical Center, Rochester, NY, USA

Pompe disease, a lysosomal storage disease caused by deficient acid alpha-glucosidase (GAA), is characterized by hypotonia, cardiomyopathy, and respiratory distress in infancy, or by proximal muscle weakness and respiratory insufficiency presenting later in childhood. We describe a unique case of Pompe disease with an intermediate presentation. A previously healthy two-year-old presented with sudden-onset weakness and inability to walk following a viral illness. A creatine kinase (CK) level was found to be markedly elevated at >3200 U/L. A muscular dystrophy was suspected and muscle biopsy was obtained. Muscle fibers had clear vacuoles and cytoplasm was replaced by glycogen, characteristic of Pompe disease. GAA activity was low in muscle (0.70 lmol/min/g; controls 1.74–9.98) and in dried blood (0.1 pmol/punch/hour; 10–49). GAA mutation analysis revealed compound heterozygosity for 871C > T and del exon 18. Enzyme replacement therapy with alglucosidase alfa was started, and he has shown clinical improvement. This case illustrates several features not typically associated with Pompe disease, including acute presentation of weakness following viral illness and markedly elevated CK levels resembling a muscular dystrophy. A diagnosis of Pompe disease should be considered in any child that has weakness and loss of milestones, regardless of the CK level or age of presentation.

Juvenile neuronal ceroid lipofuscinosis (JNCL, Batten disease) is the result of mutations in the CLN3 gene. Individuals with JNCL and Cln3 null mutant mice (Cln3 / ) raise autoantibodies against a variety of brain directed antigens and display an early neuroimmune response that precedes neuronal loss. We have recently shown that these autoantibodies can gain access to the JNCL CNS via a size selective breach in the Blood– Brain-Barrier (BBB). However, it is unclear whether this contributes directly to pathogenesis. To address this issue we have generated two different lines of Cln3 deficient mice that also lack the ability to raise B cells (Cln3 / < MT / ) or to raise CD4+ve T cells (Cln3 / CD4 / ). We have now characterised whether these double knockout mice display any difference in the onset or progression of their JNCL phenotype. As expected, Cln3 / < MT / mice display no IgG deposition within the brain and a diminished activation of astrocytes and microglia within the CNS. Similar, but less pronounced effects are evident in Cln3 / CD4 / mice. Both lines of immunodeficient Cln3 null mutant mice display a marked delay in the onset of their rotarod deficits. These data raise the question of whether immunosuppressive drugs will exhibit a similar rescue of the neuroimmune and neurologic phenotypes of murine JNCL. doi:10.1016/j.ymgme.2007.10.029

18. Enzyme replacement therapy: Transitioning care into community or home Kathy Corley, Registered Nurse, Children’s Hospital of Western Ontario/ London Health Sciences Centre, London, Ont., Canada Establishing enzyme replacement therapy in the hospital setting can pose some challenges. Transitioning care into the community or home

doi:10.1016/j.ymgme.2007.10.031

20. A severity scoring tool for Neuronopathic Gaucher disease—weighting the domains Elin Haf Davies a, Edward Giannini b, a Child BSc MSc, London, E8 1DE, UK, b Cincinatti Children’s Hospital, Cincinatti, USA Background: A Severity Scoring Tool (SST) for Neuronopathic Gaucher disease (NGD) was developed to assess disease severity. Internal reliability, feasibility, face and content (consensual and quantitative) validity have been demonstrated. Weighting of the clinical domains is required for the overall SST score to appropriately reflect disease burden.