Challenges in Cognitive Assessment of Children with MPS IIIA

Challenges in Cognitive Assessment of Children with MPS IIIA

Abstracts / Molecular Genetics and Metabolism 105 (2012) S15–S69 Conclusion: HS in plasma and urinary GAG were significantly associated with disease ...

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Abstracts / Molecular Genetics and Metabolism 105 (2012) S15–S69

Conclusion: HS in plasma and urinary GAG were significantly associated with disease severity characterized by age of loss of walking independently and age of loss of speech. Further studies are needed to assess predictive value and responses to therapy. doi:10.1016/j.ymgme.2011.11.047

Challenges in Cognitive Assessment of Children with MPS IIIA Kathleen Delaney a, Elsa Shapiro a, Chester Whitley a, Patrick Haslett b, Charles Richard b, aUniversity of Minnesota, Minneapolis, MN, USA, b Shire Human Genetic Therapies, Inc., Lexington, MA, USA Background: Mucopolysaccharidosis type IIIA (MPS IIIA) is a neurodegenerative disease with severe behavioral presentation. Assessing MPS III patients’ intellectual skills is challenging due to behavioral noncompliance and the lack of appropriate tests. A new approach to neurocognitive testing in these children is described to obtain more precise disease progression measurement. Methods: The following recomendations approaches were applied: 1) Children tested at optimum time, 2) Tests not following medical procedures, 3) Parent present in the room, 4) Tests not frustrating tester nor child, e.g. appropriate developmental level for child, 5) Parent report collected to validate direct testing, and 6) Tests performed by examiner understanding the disease to collect data reflective of the child's performance. The Bayley Scales of Infant and Toddler Development-Third Edition, Cognitive Domain, and Kaufman Assessment Battery for Children-Second Edition (KABC-II, Nonverbal Domain), tests were chosen as they cover a wide range of functioning, yielding to age equivalent scores. The Vineland Adaptive Behavior Scales, Second Edition (VABS-II) were administered to assess correlation and to help validate the findings. Results and Conclusions: Behavioral abnormalities are the direct consequences of the brain disease. Auditory agnosia (where the child does not understand verbal instructions) or motor apraxia (where the child cannot execute on demand a motor sequence that can be spontaneously produced) for example are often mistakenly identified due to noncompliant behaviors. During a natural history study sponsored by Shire Human Genetic Therapies, Inc. using this methodology, we have successfully evaluated 25 children with MPS IIIA, from age 12 months to 18 years, many with significant behavioral abnormality. A correlation was found of .95 between developmental quotient on the cognitive tests and on the Vineland given by independent examiners. Accurate developmental data sensitive to change can be obtained in children with MPS IIIA. doi:10.1016/j.ymgme.2011.11.048

Genetic Variation in a Common Biomarker Encoded By CHIT1 Ana Duarte, Diogo Ribeiro, Olga Amaral, Nat. Inst, Health Ricardo Jorge, Porto, Porto, Portugal Chitotriosidase (EC.3.2.1.14) is an enzyme secreted by activated macrophages. This chitinase is useful as a biochemical marker in several lysosomal and nonlysosomal diseases due to its increased activity in such conditions (MIM#600031). In Gaucher disease type 1 (GD, MIM#230800) patients, the chitotriosidase activity is increased in about 600-fold compared with normal controls. Chitotriosidase is not only useful as a disease severity marker but also measures the effectiveness of the therapy in GD. However, chitotriosidase gene (CHIT1, 1q31-q32) mutations modify the plasma chitotriosidase

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levels and therefore introduce a degree of variability that can be misleading. The most well known cause of chitotriosidase deficiency is the common 24 bp duplication. Nonetheless, other mutations that occur in this gene also lead to altered catalytic properties. However, as suggested by Bussink and collaborators, slight modifications in assay conditions may help avoiding such problems. In the present work we determined the frequency of two genetic variations in a group of randomly sampled Portuguese individuals representative of the country's population. The results obtained showed that about 50% of the individuals carried at least one allele with variation G102S. Since CHIT1 single nucleotide polymorphisms may be associated with particular conditions, it seems relevant to document their frequency in different populations. Furthermore, CHIT1 variants may account for additional biochemical variability and should be considered when using chitotriosidase activity as a secondary evaluation marker in diagnosis and disease prognosis. Financial support: This work was financially supported by National Funds through FCT - Fundação da Ciência e Tecnologia (MCTES – Portugal) under Project «PIC/IC/82822/2007». AJD and DR are both recipients of FCT grants. doi:10.1016/j.ymgme.2011.11.049

Gene Expression Profiling of a Mouse Model of Fabry Disease Shaalee Dworski a, Salvador Mejia-Guerrero c, Natalia Pacienza c, Bryan Au c, Jeffrey Medin a, b, c, aInstitute of Medical Science, University of Toronto, Toronto, ON, Canada, bDepartment of Medical Biophysics, University of Toronto, Toronto, Canada, cUniversity Health Network, Toronto, Canada Fabry disease is a lysosomal storage disorder due to a deficiency in α-galactosidase A (α-gal A) activity. Globotriaosylceramide (Gb3) accumulates in all cells of the body, causing several complications. The current mouse model used to study Fabry disease is deficient in α-gal A activity and exhibits Gb3 accumulation, yet it does not recapitulate the full pathology of Fabry disease, and instead seems to be protected from the effects of Gb3 accumulation. The current model is also in a mixed strain background. Recently, we made a pure NOD/SCID/Fabry mouse line. These animals also accumulate Gb3. To elucidate which genes may play a role in Gb3 protection, we compared the transcriptomes of NOD/SCID/Fabry mice with NOD/SCID controls. Comparison of the hearts, livers, and kidneys of NOD/SCID and NOD/ SCID/Fabry mice by microarray analysis revealed several genes that were up- or down- regulated by NOD/SCID/Fabry mice. Some genes were unique to an organ, while others were similarly altered in the different organs. These genes may be responsible for the protective effects against Gb3 accumulation seen in Fabry mice. Identifying the protective genes is important in two regards: 1) novel therapies targeting these genes in human Fabry patients may protect them from clinical symptoms associated with α-gal A deficiency and Gb3 accumulation, and 2) these genes could be altered in the Fabry mouse model to diminish the protection and create a mouse model that better recapitulates the human clinical symptoms. doi:10.1016/j.ymgme.2011.11.050

Assessment of Disease Severity in Late Infantile Neuronal Ceroid Lipofuscinosis Using Whole Brain Multiparametric Magnetic Resonance Imaging Jonathan Dyke a, Dolan Sondhi c, Henning Voss a, Dikoma Shungu a, Kaleb Yohay b, Stefan Worgall b, Neil Hackett c, Charlene Hollmann c,