genetic variation in a common biomarker encoded by chit1
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Conclusion: HS in plasma and urinary GAG were significantlyassociated with disease severity characterized by age of loss ofwalking independently and age of loss of speech. Further studies areneeded 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,bShire Human Genetic Therapies, Inc., Lexington, MA, USA
Background: Mucopolysaccharidosis type IIIA (MPS IIIA) is aneurodegenerative disease with severe behavioral presentation.Assessing MPS III patients’ intellectual skills is challenging due tobehavioral noncompliance and the lack of appropriate tests. A newapproach to neurocognitive testing in these children is described toobtain more precise disease progression measurement.
Methods: The following recomendations approaches were applied:1) Children tested at optimum time, 2) Tests not following medicalprocedures, 3) Parent present in the room, 4) Tests not frustrating testernor child, e.g. appropriate developmental level for child, 5) Parent reportcollected to validate direct testing, and 6) Tests performed by examinerunderstanding the disease to collect data reflective of the child'sperformance.
The Bayley Scales of Infant and Toddler Development-ThirdEdition, Cognitive Domain, and Kaufman Assessment Battery forChildren-Second Edition (KABC-II, Nonverbal Domain), tests werechosen as they cover a wide range of functioning, yielding to ageequivalent scores. The Vineland Adaptive Behavior Scales, SecondEdition (VABS-II) were administered to assess correlation and to helpvalidate the findings.
Results and Conclusions: Behavioral abnormalities are the directconsequences of the brain disease. Auditory agnosia (where the childdoes not understand verbal instructions) or motor apraxia (wherethe child cannot execute on demand a motor sequence that can bespontaneously produced) for example are often mistakenly identifieddue to noncompliant behaviors. During a natural history studysponsored by Shire Human Genetic Therapies, Inc. using thismethodology, we have successfully evaluated 25 children with MPSIIIA, from age 12 months to 18 years, many with significant behavioralabnormality. A correlation was found of .95 between developmentalquotient on the cognitive tests and on the Vineland given byindependent examiners. Accurate developmental data sensitive tochange 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 activatedmacrophages. This chitinase is useful as a biochemical marker inseveral lysosomal and nonlysosomal diseases due to its increasedactivity in such conditions (MIM#600031). In Gaucher disease type 1(GD, MIM#230800) patients, the chitotriosidase activity is increasedin about 600-fold compared with normal controls. Chitotriosidase isnot only useful as a disease severity marker but also measures theeffectiveness of the therapy in GD. However, chitotriosidase gene(CHIT1, 1q31-q32) mutations modify the plasma chitotriosidase
levels and therefore introduce a degree of variability that can bemisleading. The most well known cause of chitotriosidase deficiencyis the common 24 bp duplication. Nonetheless, other mutations thatoccur in this gene also lead to altered catalytic properties. However,as suggested by Bussink and collaborators, slight modifications inassay conditions may help avoiding such problems. In the presentwork we determined the frequency of two genetic variations in agroup of randomly sampled Portuguese individuals representative ofthe 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 withparticular conditions, it seems relevant to document their frequencyin different populations. Furthermore, CHIT1 variants may account foradditional biochemical variability and should be considered whenusing chitotriosidase activity as a secondary evaluation marker indiagnosis and disease prognosis.
Financial support: This work was financially supported by NationalFunds through FCT - Fundação da Ciência e Tecnologia (MCTES –
Portugal) under Project «PIC/IC/82822/2007». AJD and DR are bothrecipients 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, Universityof 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 inα-galactosidase A (α-gal A) activity. Globotriaosylceramide (Gb3)accumulates in all cells of the body, causing several complications. Thecurrent mouse model used to study Fabry disease is deficient in α-galA activity and exhibits Gb3 accumulation, yet it does not recapitulatethe full pathology of Fabry disease, and instead seems to be protectedfrom the effects of Gb3 accumulation. The current model is also in amixed strain background. Recently, we made a pure NOD/SCID/Fabrymouse line. These animals also accumulate Gb3. To elucidate whichgenes may play a role in Gb3 protection, we compared thetranscriptomes 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 thatwere up- or down- regulated by NOD/SCID/Fabry mice. Some geneswere unique to an organ, while others were similarly altered in thedifferent organs. These genes may be responsible for the protectiveeffects against Gb3 accumulation seen in Fabry mice. Identifying theprotective genes is important in two regards: 1) novel therapiestargeting these genes in human Fabry patients may protect them fromclinical symptoms associated with α-gal A deficiency and Gb3accumulation, and 2) these genes could be altered in the Fabry mousemodel to diminish the protection and create a mouse model that betterrecapitulates the human clinical symptoms.
doi:10.1016/j.ymgme.2011.11.050
Assessment of Disease Severity in Late Infantile Neuronal CeroidLipofuscinosis Using Whole Brain Multiparametric MagneticResonance 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,
Abstracts / Molecular Genetics and Metabolism 105 (2012) S15–S69 S27