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Diffusion tensor imaging: Study of white-matter brain in paediatric patients with Gaucher disease
Abstracts / Molecular Genetics and Metabolism 102 (2011) S3–S47
human primary fibroblasts from MPS I, II, and III patients indicate that inhibiting the 2-O sulfation of heparan sulfate can reduce the lysosomal accumulation of this glycan. Using a cell-based high throughput screen, we have identified a set of compounds that inhibit the sulfation of heparan sulfate and reduce lysosomal accumulation of GAGs in MPS cells. From these compounds, we identified a blood-brain barrier penetrant compound that reduces lysosomal accumulation of GAGs in the central nervous system in the mouse model of MPS II and IIIA with no adverse tolerability observed. To optimize potency, PK, and other druglike properties, we then synthesized and tested a number of analogs and identified compounds with improved in vitro potency in cultured human MPS fibroblasts while retaining excellent blood-brain barrier penetration. Ongoing lead optimization activities are aimed at identifying a clinical candidate drug for IND enabling activities and human clinical trials. When successfully completed, this research will have enabled the first small molecule therapy capable of addressing the CNS and other unmet needs in patients with MPS I, II, and III. doi:10.1016/j.ymgme.2010.11.042
Validation of dried blood spots samples to diagnose Mucopolysaccharidosis type VI in a Brazilian specialized center Vania D'Almeidaa, Karen Mullera, Joyce Yamamotoa, Marcelo Kerstenetzkyb, Ana Maria Martinsa, aUniversidade Federal de São Paulo, SP
Diffusion tensor imaging: Study of white-matter brain in paediatric patients with Gaucher disease Elin Daviesa, Kiran Seunarinea, Chris Clarka, Vellodi Ashokb, aInstitute of Child Health, London, London, UK, bGreat Ormond Street Hospital, London, UK
S13
Introduction: Markers of neurological dysfunction in Neuronopathic Gaucher Disease (NGD) are lacking. Diffusion tensor imaging (DTI) is a technique which allows us to study the microstructure of white matter brain. Methods: DTI was performed on 4 NGD (1 boy, 3 girls, 12.2 years (±3.5)) and 3 Type I patients (all boys, 9.5 years (±3.3)). Fractional anisotropy (FA), mean diffusivity (MD), axial (axial) and radial (radial) diffusivity maps were calculated. Tract-Based Spatial Statistics (TBSS) were used to perform a voxel-wise statistical analysis of the main white matter structures. Data was compared to age-sex matched control groups. Data were acquired on a 1.5 T Siemens Avanto scanner. 20 diffusion-weighted images were acquired at b = 1000 s mm2 along with 3 images at b = 0 for normalisation. Images were processed using FSL to correct for eddy-currents, brain extraction and DTI reconstruction. Results: The TBSS findings suggest the presence of microstructural white matter changes in NGD patients, primarily in the middle cerebellar peduncles with a decrease in FA and an increase in radial and MD. There was also an increase in axial diffusivity; however the effect was much smaller than with other indices. In contrast, Type I patients had diffuse changes but showed no significant difference in the cerebellar peduncles. Discussion: This study provides new insight into paedaitric Gaucher brain pathophysiology, and suggests that DTI may be an attractive surrogate marker, worthy of further exploration. doi:10.1016/j.ymgme.2010.11.044
Defining the Gait profile of children with Neuronopathic Gaucher disease Elin Davies, Lucy Alderson, Michelle Wood, Ashok Vellodi, Institute of Child Health, London, London, UK Introduction: Neuronopathic Gaucher Disease (NGD) is an inherited lysosomal disorder. Clinical features include horizontal gaze palsy, epilepsy and ataxia, however there is great heterogeneity. There are currently no validated surrogate markers of disease. Aim: To evaluate the use of the GAITRite walkway to define their gait. Methods: Nine NGD patients were studied and 5 Type I Gaucher children served as a control group. Results: The mean age for NGD cohort was 10.2 years (SD4.1) and 10.6 years (SD3.4) for the Type I cohort. Five of the NGD cohort was L444P/L444P. Gait parameters explored were Velocity (cm/s), Cadence (Steps/ minute), Step Time (cms), Step Time (seconds), Single and Double Support (% of gait cycle), Base of Support (cms). Direct group comparison identified a statistical significance in Velocity (p0.005), Step Time (p0.044), Single Support (p0.044) and Double Support (p0.040). This significance remains when Z scores generated from LMS centiles are utilised. LMS centiles summarise the changing distribution of a normal population by three curves representing the median (M), coefficient of variation (S) and skewness (L). Cadence Z score becomes statistically significant (p0.046). Discussion: Deviations in the NGD gait profile suggest that the patients reduce their velocity and increase their time on both feet (double support) as a compensatory measure to improve stability. There was no difference in Base of Support despite commonly reported ‘wide-based gait’ in ataxic children. The GAITRite is sensitive to identify and quantify subtle abnormalities not seen clinically. doi:10.1016/j.ymgme.2010.11.045
Q10
human primary fibroblasts from MPS I, II, and III patients indicate that inhibiting the 2-O sulfation of heparan sulfate can reduce the lysosomal accumulation of this glycan. Using a cell-based high throughput screen, we have identified a set of compounds that inhibit the sulfation of heparan sulfate and reduce lysosomal accumulation of GAGs in MPS cells. From these compounds, we identified a blood-brain barrier penetrant compound that reduces lysosomal accumulation of GAGs in the central nervous system in the mouse model of MPS II and IIIA with no adverse tolerability observed. To optimize potency, PK, and other druglike properties, we then synthesized and tested a number of analogs and identified compounds with improved in vitro potency in cultured human MPS fibroblasts while retaining excellent blood-brain barrier penetration. Ongoing lead optimization activities are aimed at identifying a clinical candidate drug for IND enabling activities and human clinical trials. When successfully completed, this research will have enabled the first small molecule therapy capable of addressing the CNS and other unmet needs in patients with MPS I, II, and III. doi:10.1016/j.ymgme.2010.11.042
Validation of dried blood spots samples to diagnose Mucopolysaccharidosis type VI in a Brazilian specialized center Vania D'Almeidaa, Karen Mullera, Joyce Yamamotoa, Marcelo Kerstenetzkyb, Ana Maria Martinsa, aUniversidade Federal de São Paulo, SP
Diffusion tensor imaging: Study of white-matter brain in paediatric patients with Gaucher disease Elin Daviesa, Kiran Seunarinea, Chris Clarka, Vellodi Ashokb, aInstitute of Child Health, London, London, UK, bGreat Ormond Street Hospital, London, UK
S13
Introduction: Markers of neurological dysfunction in Neuronopathic Gaucher Disease (NGD) are lacking. Diffusion tensor imaging (DTI) is a technique which allows us to study the microstructure of white matter brain. Methods: DTI was performed on 4 NGD (1 boy, 3 girls, 12.2 years (±3.5)) and 3 Type I patients (all boys, 9.5 years (±3.3)). Fractional anisotropy (FA), mean diffusivity (MD), axial (axial) and radial (radial) diffusivity maps were calculated. Tract-Based Spatial Statistics (TBSS) were used to perform a voxel-wise statistical analysis of the main white matter structures. Data was compared to age-sex matched control groups. Data were acquired on a 1.5 T Siemens Avanto scanner. 20 diffusion-weighted images were acquired at b = 1000 s mm2 along with 3 images at b = 0 for normalisation. Images were processed using FSL to correct for eddy-currents, brain extraction and DTI reconstruction. Results: The TBSS findings suggest the presence of microstructural white matter changes in NGD patients, primarily in the middle cerebellar peduncles with a decrease in FA and an increase in radial and MD. There was also an increase in axial diffusivity; however the effect was much smaller than with other indices. In contrast, Type I patients had diffuse changes but showed no significant difference in the cerebellar peduncles. Discussion: This study provides new insight into paedaitric Gaucher brain pathophysiology, and suggests that DTI may be an attractive surrogate marker, worthy of further exploration. doi:10.1016/j.ymgme.2010.11.044
Defining the Gait profile of children with Neuronopathic Gaucher disease Elin Davies, Lucy Alderson, Michelle Wood, Ashok Vellodi, Institute of Child Health, London, London, UK Introduction: Neuronopathic Gaucher Disease (NGD) is an inherited lysosomal disorder. Clinical features include horizontal gaze palsy, epilepsy and ataxia, however there is great heterogeneity. There are currently no validated surrogate markers of disease. Aim: To evaluate the use of the GAITRite walkway to define their gait. Methods: Nine NGD patients were studied and 5 Type I Gaucher children served as a control group. Results: The mean age for NGD cohort was 10.2 years (SD4.1) and 10.6 years (SD3.4) for the Type I cohort. Five of the NGD cohort was L444P/L444P. Gait parameters explored were Velocity (cm/s), Cadence (Steps/ minute), Step Time (cms), Step Time (seconds), Single and Double Support (% of gait cycle), Base of Support (cms). Direct group comparison identified a statistical significance in Velocity (p0.005), Step Time (p0.044), Single Support (p0.044) and Double Support (p0.040). This significance remains when Z scores generated from LMS centiles are utilised. LMS centiles summarise the changing distribution of a normal population by three curves representing the median (M), coefficient of variation (S) and skewness (L). Cadence Z score becomes statistically significant (p0.046). Discussion: Deviations in the NGD gait profile suggest that the patients reduce their velocity and increase their time on both feet (double support) as a compensatory measure to improve stability. There was no difference in Base of Support despite commonly reported ‘wide-based gait’ in ataxic children. The GAITRite is sensitive to identify and quantify subtle abnormalities not seen clinically. doi:10.1016/j.ymgme.2010.11.045
Q10