- Email: [email protected]
Diagnosing communicating hydrocephalus in mucopolysaccharidoses: Correlation between cerebrospinal fluid flow imaging and lumbar pressure studies
Abstracts / Molecular Genetics and Metabolism 114 (2015) S11–S130
59 Rapid kinetics of β-cyclodextrin entering and exiting cells: Implication of its mechanism on reduction of cholesterol accumulation in Niemann–Pick disease type C cells Sheng Dai, Andrés E. Dulcey, Manju Swaroop, Juan Marugan, John McKew, Wei Zheng, National Institutes of Health, Bethesda, MD, USA
doi:10.1016/j.ymgme.2014.12.062
61 Diagnosing communicating hydrocephalus in mucopolysaccharidoses: Correlation between cerebrospinal fluid flow imaging and lumbar pressure studies
DP
β-Cyclodextrin is a seven-membered sugar ring molecule with hydrophobic inside and hydrophilic outside that is commonly used for dissolving and delivering of hydrophobic compounds. It has been reported that beta-cyclodextrins reduce lysosomal cholesterol accumulation in Niemann–Pick disease type C (NPC). The water-soluble cyclodextrin may enter cells through endocytosis and exit cells by exocytosis. We have employed a bodipy-labeled beta-cyclodextrin to study the kinetics of this molecule movement in cells as well as whether cyclodextrin transports cholesterol molecule out of the cells. We found that cyclodextrins entered the cells rapidly and reached a plateau at ~2 h. The cyclodextrins also leave cells quickly with 90% of labeled cyclodextrin out of cells after a cell wash. These results demonstrated that beta-cyclodextrin enters cells through endocytosis and exit cells by exocytosis. We also found that betacyclodextrin dissolved cholesterols could not be loaded into the NPC1 iPS cell differentiated neuronal cells, indicating that cyclodextrins may take the cholesterol molecule out of cells. We are currently studying the effect of beta-cyclodextrin on removing lysosomal accumulated cholesterols and on the mechanism of cyclodextrin for the reduction of autophagosomes. Therefore, we will present new results for the mechanism of action for cyclodextrin on the reduction of lysosomal cholesterol accumulation in NPC cells.
OF
doi:10.1016/j.ymgme.2014.12.060
addition, the infantile cases presented hepatosplenomegaly and the adult cases presented psychiatric symptoms. The chitotriosidase at diagnosis ranged from 72 to 3300 nmol/h/mL. The Filipin test in fibroblasts was positive in 4/6 patients, and inconclusive in 1/6 cases. Molecular analysis of the NPC1 gene showed pathogenic mutations in 5/6 patients (2 mutations are not previously described in the literature). Familial recurrence was observed in 3/9 cases and consanguinity was present in 2/6 families. Miglustat was started in 7/9 patients (2 infantile, 2 juvenile and 3 adult), and is being generally well tolerated. The disease progression was stabilized in 5/7 patients who received Miglustat. One patient with the infantile form started treatment recently and the other infantile patient deceased. This report illustrates the broad heterogeneity of NPC presentation, even when a small number of patients are analyzed, and stresses the need of increasing awareness about this disease and of making available the appropriate tools for the laboratory diagnosis, especially important as a specific treatment is available.
RO
stabilization of the frequency). All patients underwent polissonography, where 91% showed at least one kind of abnormality, 50% of those stabilized or showed some improvement during ERT. A significant number of patients presented marked improvement in organ function, and physical manifestations, specially coarse facies, cardiac, respiratory and articular disease, showing that ERT reduces GAG constant accumulation in these tissues. In our population, ERT showed to be effective in preventing progression of the disease in most affected organs, helping to improve the patients' and their families' quality of life.
S35
TE
Carolina Fischinger Moura de Souza, Amauri Dalla Corte, Filippo Vairo, Mauricio Anés, Leonardo Modesti Vedolin, Monica Moraes Ferreira, Adriano de Alencastro Guimaraes Aguzzoli, Solanger Graciana Paulão Perrone, Andressa Federhen, Roberto Giugliani, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
RR
EC
Introduction: Hydrocephalus in patients with mucopolysaccharidosis (MPS) is remarkable for two reasons: 1) it is one of the few treatable causes of intracranial hypertension, and 2) neuroradiologists, neurologists and neurosurgeons are usually involved in making the diagnosis which radiographically is not easily distinguishable from atrophy. Cerebrospinal fluid (CSF) flow study is a noninvasive imaging technique that is useful for the evaluation of patients with hydrocephalus, which is a common finding in mucopolysaccharidosis (MPS). Lumbar subarachnoid pressure higher than 20 cm H2O can be considered indicative of hydrocephalus. Objective: To distinguish ventricles dilatation from sulcal enlargement in MPS patients and characterize hydrocephalus by using cerebrospinal fluid (CSF) lumbar pressure manometry and aqueductal CSF flow magnetic resonance imaging (MRI) study. Methods: We performed a CSF flow study by phase-contrast MRI followed by a standard lumbar puncture with the CSF opening pressure assessment in 15 patients: MPS type I in 3 patients, MPS type II in 7 patients, MPS type III in 3 patients and MPS type IVA in 2 patients. The age range was 1 to 30 years, 12 males and 3 females. Results: The most frequent findings were pyramidal signs in 7 patients and macrocephaly in 8 patients. Only three patients had no cognitive impairment. The MRI abnormalities were observed in all patients. The most frequent MRI findings were dilated perivascular spaces in 10 patients, white matter changes in 10 patients, ventricle enlargement in 7 patients and craniovertebral junction stenosis in 5 patients. Of the 7 patients who were suspected of hydrocephalus, hyperdynamic aqueductal CSF flow was obtained in 4 of them and 3 patients showed CSF lumbar pressure values above 200 mm H2O. On the other hand, in 4 patients with no typical ventriculomegaly elevated CSF pressure values were obtained. Conclusions: A better understanding of the pathophysiology of hydrocephalus in MPS patients will undoubtedly lead to better patient selection and treatment. Although this is the first description
CO
doi:10.1016/j.ymgme.2014.12.061
60 Broad clinical and laboratory spectrum found in 9 Niemann–Pick disease type C Southern Brazilian patients
UN
Carolina Fischinger Moura de Souzaa, Karina Carvalho Donisa, Jonas Sautea, Filippo Vairoa, Fernanda Timma, Maria Luiza Saraiva-Pereirab, Mirela Gila, Marcia Polese Bonatoa, Roberto Giugliania, aHospital de Clínicas de Porto Alegre, Porto Alegre, Brazil, bUniversidade Federal do Rio Grande do Sul, Porto Alegre, Brazil Niemann–Pick disease type C (NPC) is an autosomal recessive disease related to defects on cholesterol trafficking. We describe different forms of disease presentation, laboratory findings and response to Miglustat therapy in 9 NPC patients evaluated in Porto Alegre, Brazil. Patients were 4 females and 5 males, being 3 with adult form, 2 with juvenile form and 4 with infantile form (two deceased). The age at diagnosis ranged from 7 months to 32 years. All patients were referred for investigation due to neurological regression. In
Abstracts / Molecular Genetics and Metabolism 114 (2015) S11–S130
doi:10.1016/j.ymgme.2014.12.063
62 Predictors of fracture in treated Gaucher disease patients Patrick Deegana, Judy Kempf b, aDepartment of Medicine, Addenbrooke's Hospital, Cambridge, UK, bGenzyme, a Sanofi company, Cambridge, MA, USA
CO
RR
EC
TE
DP
Skeletal complications, particularly fracture, can be one of the most debilitating consequences of Gaucher disease (GD). Understanding the risk factors for fracture and the relationship to timing of initiation of treatment is important for successful evaluation and management of patients. The International Collaborative Gaucher Group (ICGG) Gaucher Registry is a multinational, observational study (sponsored by Genzyme, a Sanofi company, Cambridge, MA) that captures clinical outcomes in both treated and untreated GD patients. Descriptive statistics and an adjusted logistic regression model were used to evaluate demographics and risk factors in patients enrolled in the ICGG Registry with GD type 1 who had experienced a fracture. A total of 4047 patients with GD type 1 in the ICGG Registry who had received imiglucerase had sufficient bone and splenectomy data for analyses. Of these, 46% were male, the median age of diagnosis was 15 years of age, and 336 patients (8%) had experienced a fracture during treatment. Splenectomized patients were nearly twice as likely to have a fracture compared to those who were not (OR 1.930; p = b0.0001). The presence of bone pain or bone crisis (acute pain requiring immobilization, narcotics, and accompanied by periosteal elevation, elevated WBC count, fever and/or debilitation of N3 days) was a predictor of fracture, even if reported considerably prior to the fracture itself. Patients with bone pain were 2.5 times more likely to have a fracture (OR 2.683; p = b0.0001); those with bone crises were nearly twice as likely (OR 1.739; p = b0.0004). Additionally, early treatment decreased fracture risk. Patients who did not begin treatment until after the age of 25 were 30% (OR 1.373; p = 0.0132) more likely to have a fracture. The 3711 patients who did not have a fracture were diagnosed (median age: 14 years) and treated (median age: 27 years) younger than the 336 with a fracture who were diagnosed (median age: 17.5 years) and treated (median age: 37 years) later. Understanding risk factors, symptoms, and treatment patterns is important to avoid potential fractures. Splenectomy, bone pain, and bone crisis substantially elevate risk of fractures in patients on therapy, and should be considered early warning signs. Younger age at treatment initiation lowers the risk of fracture, suggesting that developing bone pathology may be interrupted when early treatment is provided.
hematopoietic stem cell transplants using cells from matched donors. While these therapies focus on the correction of either the defective cells, ameliorate the effects or the biochemical activity of the defective LSD enzyme, genome editing strategies aim to permanently modify patient cells by repairing or complementing the defect at the genetic level. In particular, genome editing utilizing engineered zinc finger nucleases (ZFNs) to genetically modify liver hepatocytes is a promising approach to achieve long-term expression of therapeutic transgenes in vivo. In this technology a pair of sequence-specific ZFNs introduces a DNA double-strand break at the target locus, which allows subsequent integration of a therapeutic cDNA. We have previously demonstrated adeno-associated vector (AAV)-mediated in vivo targeting of the endogenous murine albumin locus as a “safe harbor” for synthesis of blood coagulation factors, resulting in sufficient Factor VIII and Factor IX to correct the clotting defect in hemophilic mice. Targeted insertion of the donor sequence into the genome offers multiple advantages. First, we are able to exploit the high transcriptional activity of the native albumin enhancer/promoter. Second, liver hepatocytes are stably modified to potentially allow stable, long-term expression of the inserted therapeutic transgene. Third, utilization of an endogenous promoter obviates the need for inclusion of a promoter in the donor construct, allowing packaging of larger transgenes that may not normally package efficiently in AAV. In our studies we co-delivered mouse albumin specific ZFNs with a donor construct encoding a partial cDNA for either human IDS (mutated in Hunter disease), IDUA (Hurler disease), or GBA (Gaucher disease) using AAV in wild type mice. We demonstrate stable integration of the IDS, IDUA and GBA donor cDNAs at the albumin locus, which resulted in liver-specific expression and secretion of these proteins into plasma. This led to a 4-fold (GBA), 10fold (IDUA) or 100-fold (IDS) increase in detectable enzymatic activity in the plasma, demonstrating that transgenes expressed from albumin are not only secreted from liver hepatocytes but are also enzymatically active. For IDS and IDUA, this correlated well with increased enzymatic activity and protein expression in the liver, and increased enzymatic activity was also detected in secondary tissues like the spleen. IDS, IDUA or GBA expression remained stable in mice for the duration of the study (1–2 months), suggesting that this process is well-tolerated. In summary, we have demonstrated proof of concept data using our in vivo protein replacement platform targeting the albumin locus to express different factors involved in lysosomal disease. Together our results support the further investigation of genome editing at the albumin locus as a novel method for in vivo protein replacement.
OF
using quantitative CSF flow MRI study and CSF lumbar pressure manometry to diagnose high intracranial pressure in MPS patients larger studies must be done to best determine which patients will respond positively to shunting.
RO
S36
UN
doi:10.1016/j.ymgme.2014.12.064
63 ZFN-mediated genome editing of albumin “safe harbor” in vivo results in supraphysiological levels of human IDS, IDUA and GBA in mice Russell DeKelver, Michelle Rohde, Susan Tom, Yolanda Santiago, Scott Sproul, Philip D. Gregory, Michael C. Holmes, Thomas Wechsler, Sangamo BioSciences, Richmond, CA, USA Current therapies for lysosomal diseases (LSD) include enzyme replacement strategies (ERT), substrate reduction therapies and allogeneic
doi:10.1016/j.ymgme.2014.12.065
64 Methods for cognitive assessment of children and adults with lysosomal diseases Kathleen A. Delaney, Elsa G. Shapiro, University of Minnesota, Minneapolis, MN, USA New treatments for diseases that affect brain require sensitive measures of disease progression and treatment outcome. Genetic diseases affecting the brain are associated with altered neurochemical, neurophysiological, and neurodevelopment processes that result in disease-specific neurocognitive and neurobehavioral phenotypes. The following approaches resulted from five years of a longitudinal study of the mucopolysaccharidoses but also apply to other lysosomal diseases. Measurement of neurocognitive growth and decline in brain structure and function require alterations in the methods of assessment due to chronological age and disease factors such as motor and sensory impairment and low cognitive functioning. Success in identifying disease-specific measures sensitive to disease progression
59 Rapid kinetics of β-cyclodextrin entering and exiting cells: Implication of its mechanism on reduction of cholesterol accumulation in Niemann–Pick disease type C cells Sheng Dai, Andrés E. Dulcey, Manju Swaroop, Juan Marugan, John McKew, Wei Zheng, National Institutes of Health, Bethesda, MD, USA
doi:10.1016/j.ymgme.2014.12.062
61 Diagnosing communicating hydrocephalus in mucopolysaccharidoses: Correlation between cerebrospinal fluid flow imaging and lumbar pressure studies
DP
β-Cyclodextrin is a seven-membered sugar ring molecule with hydrophobic inside and hydrophilic outside that is commonly used for dissolving and delivering of hydrophobic compounds. It has been reported that beta-cyclodextrins reduce lysosomal cholesterol accumulation in Niemann–Pick disease type C (NPC). The water-soluble cyclodextrin may enter cells through endocytosis and exit cells by exocytosis. We have employed a bodipy-labeled beta-cyclodextrin to study the kinetics of this molecule movement in cells as well as whether cyclodextrin transports cholesterol molecule out of the cells. We found that cyclodextrins entered the cells rapidly and reached a plateau at ~2 h. The cyclodextrins also leave cells quickly with 90% of labeled cyclodextrin out of cells after a cell wash. These results demonstrated that beta-cyclodextrin enters cells through endocytosis and exit cells by exocytosis. We also found that betacyclodextrin dissolved cholesterols could not be loaded into the NPC1 iPS cell differentiated neuronal cells, indicating that cyclodextrins may take the cholesterol molecule out of cells. We are currently studying the effect of beta-cyclodextrin on removing lysosomal accumulated cholesterols and on the mechanism of cyclodextrin for the reduction of autophagosomes. Therefore, we will present new results for the mechanism of action for cyclodextrin on the reduction of lysosomal cholesterol accumulation in NPC cells.
OF
doi:10.1016/j.ymgme.2014.12.060
addition, the infantile cases presented hepatosplenomegaly and the adult cases presented psychiatric symptoms. The chitotriosidase at diagnosis ranged from 72 to 3300 nmol/h/mL. The Filipin test in fibroblasts was positive in 4/6 patients, and inconclusive in 1/6 cases. Molecular analysis of the NPC1 gene showed pathogenic mutations in 5/6 patients (2 mutations are not previously described in the literature). Familial recurrence was observed in 3/9 cases and consanguinity was present in 2/6 families. Miglustat was started in 7/9 patients (2 infantile, 2 juvenile and 3 adult), and is being generally well tolerated. The disease progression was stabilized in 5/7 patients who received Miglustat. One patient with the infantile form started treatment recently and the other infantile patient deceased. This report illustrates the broad heterogeneity of NPC presentation, even when a small number of patients are analyzed, and stresses the need of increasing awareness about this disease and of making available the appropriate tools for the laboratory diagnosis, especially important as a specific treatment is available.
RO
stabilization of the frequency). All patients underwent polissonography, where 91% showed at least one kind of abnormality, 50% of those stabilized or showed some improvement during ERT. A significant number of patients presented marked improvement in organ function, and physical manifestations, specially coarse facies, cardiac, respiratory and articular disease, showing that ERT reduces GAG constant accumulation in these tissues. In our population, ERT showed to be effective in preventing progression of the disease in most affected organs, helping to improve the patients' and their families' quality of life.
S35
TE
Carolina Fischinger Moura de Souza, Amauri Dalla Corte, Filippo Vairo, Mauricio Anés, Leonardo Modesti Vedolin, Monica Moraes Ferreira, Adriano de Alencastro Guimaraes Aguzzoli, Solanger Graciana Paulão Perrone, Andressa Federhen, Roberto Giugliani, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
RR
EC
Introduction: Hydrocephalus in patients with mucopolysaccharidosis (MPS) is remarkable for two reasons: 1) it is one of the few treatable causes of intracranial hypertension, and 2) neuroradiologists, neurologists and neurosurgeons are usually involved in making the diagnosis which radiographically is not easily distinguishable from atrophy. Cerebrospinal fluid (CSF) flow study is a noninvasive imaging technique that is useful for the evaluation of patients with hydrocephalus, which is a common finding in mucopolysaccharidosis (MPS). Lumbar subarachnoid pressure higher than 20 cm H2O can be considered indicative of hydrocephalus. Objective: To distinguish ventricles dilatation from sulcal enlargement in MPS patients and characterize hydrocephalus by using cerebrospinal fluid (CSF) lumbar pressure manometry and aqueductal CSF flow magnetic resonance imaging (MRI) study. Methods: We performed a CSF flow study by phase-contrast MRI followed by a standard lumbar puncture with the CSF opening pressure assessment in 15 patients: MPS type I in 3 patients, MPS type II in 7 patients, MPS type III in 3 patients and MPS type IVA in 2 patients. The age range was 1 to 30 years, 12 males and 3 females. Results: The most frequent findings were pyramidal signs in 7 patients and macrocephaly in 8 patients. Only three patients had no cognitive impairment. The MRI abnormalities were observed in all patients. The most frequent MRI findings were dilated perivascular spaces in 10 patients, white matter changes in 10 patients, ventricle enlargement in 7 patients and craniovertebral junction stenosis in 5 patients. Of the 7 patients who were suspected of hydrocephalus, hyperdynamic aqueductal CSF flow was obtained in 4 of them and 3 patients showed CSF lumbar pressure values above 200 mm H2O. On the other hand, in 4 patients with no typical ventriculomegaly elevated CSF pressure values were obtained. Conclusions: A better understanding of the pathophysiology of hydrocephalus in MPS patients will undoubtedly lead to better patient selection and treatment. Although this is the first description
CO
doi:10.1016/j.ymgme.2014.12.061
60 Broad clinical and laboratory spectrum found in 9 Niemann–Pick disease type C Southern Brazilian patients
UN
Carolina Fischinger Moura de Souzaa, Karina Carvalho Donisa, Jonas Sautea, Filippo Vairoa, Fernanda Timma, Maria Luiza Saraiva-Pereirab, Mirela Gila, Marcia Polese Bonatoa, Roberto Giugliania, aHospital de Clínicas de Porto Alegre, Porto Alegre, Brazil, bUniversidade Federal do Rio Grande do Sul, Porto Alegre, Brazil Niemann–Pick disease type C (NPC) is an autosomal recessive disease related to defects on cholesterol trafficking. We describe different forms of disease presentation, laboratory findings and response to Miglustat therapy in 9 NPC patients evaluated in Porto Alegre, Brazil. Patients were 4 females and 5 males, being 3 with adult form, 2 with juvenile form and 4 with infantile form (two deceased). The age at diagnosis ranged from 7 months to 32 years. All patients were referred for investigation due to neurological regression. In
Abstracts / Molecular Genetics and Metabolism 114 (2015) S11–S130
doi:10.1016/j.ymgme.2014.12.063
62 Predictors of fracture in treated Gaucher disease patients Patrick Deegana, Judy Kempf b, aDepartment of Medicine, Addenbrooke's Hospital, Cambridge, UK, bGenzyme, a Sanofi company, Cambridge, MA, USA
CO
RR
EC
TE
DP
Skeletal complications, particularly fracture, can be one of the most debilitating consequences of Gaucher disease (GD). Understanding the risk factors for fracture and the relationship to timing of initiation of treatment is important for successful evaluation and management of patients. The International Collaborative Gaucher Group (ICGG) Gaucher Registry is a multinational, observational study (sponsored by Genzyme, a Sanofi company, Cambridge, MA) that captures clinical outcomes in both treated and untreated GD patients. Descriptive statistics and an adjusted logistic regression model were used to evaluate demographics and risk factors in patients enrolled in the ICGG Registry with GD type 1 who had experienced a fracture. A total of 4047 patients with GD type 1 in the ICGG Registry who had received imiglucerase had sufficient bone and splenectomy data for analyses. Of these, 46% were male, the median age of diagnosis was 15 years of age, and 336 patients (8%) had experienced a fracture during treatment. Splenectomized patients were nearly twice as likely to have a fracture compared to those who were not (OR 1.930; p = b0.0001). The presence of bone pain or bone crisis (acute pain requiring immobilization, narcotics, and accompanied by periosteal elevation, elevated WBC count, fever and/or debilitation of N3 days) was a predictor of fracture, even if reported considerably prior to the fracture itself. Patients with bone pain were 2.5 times more likely to have a fracture (OR 2.683; p = b0.0001); those with bone crises were nearly twice as likely (OR 1.739; p = b0.0004). Additionally, early treatment decreased fracture risk. Patients who did not begin treatment until after the age of 25 were 30% (OR 1.373; p = 0.0132) more likely to have a fracture. The 3711 patients who did not have a fracture were diagnosed (median age: 14 years) and treated (median age: 27 years) younger than the 336 with a fracture who were diagnosed (median age: 17.5 years) and treated (median age: 37 years) later. Understanding risk factors, symptoms, and treatment patterns is important to avoid potential fractures. Splenectomy, bone pain, and bone crisis substantially elevate risk of fractures in patients on therapy, and should be considered early warning signs. Younger age at treatment initiation lowers the risk of fracture, suggesting that developing bone pathology may be interrupted when early treatment is provided.
hematopoietic stem cell transplants using cells from matched donors. While these therapies focus on the correction of either the defective cells, ameliorate the effects or the biochemical activity of the defective LSD enzyme, genome editing strategies aim to permanently modify patient cells by repairing or complementing the defect at the genetic level. In particular, genome editing utilizing engineered zinc finger nucleases (ZFNs) to genetically modify liver hepatocytes is a promising approach to achieve long-term expression of therapeutic transgenes in vivo. In this technology a pair of sequence-specific ZFNs introduces a DNA double-strand break at the target locus, which allows subsequent integration of a therapeutic cDNA. We have previously demonstrated adeno-associated vector (AAV)-mediated in vivo targeting of the endogenous murine albumin locus as a “safe harbor” for synthesis of blood coagulation factors, resulting in sufficient Factor VIII and Factor IX to correct the clotting defect in hemophilic mice. Targeted insertion of the donor sequence into the genome offers multiple advantages. First, we are able to exploit the high transcriptional activity of the native albumin enhancer/promoter. Second, liver hepatocytes are stably modified to potentially allow stable, long-term expression of the inserted therapeutic transgene. Third, utilization of an endogenous promoter obviates the need for inclusion of a promoter in the donor construct, allowing packaging of larger transgenes that may not normally package efficiently in AAV. In our studies we co-delivered mouse albumin specific ZFNs with a donor construct encoding a partial cDNA for either human IDS (mutated in Hunter disease), IDUA (Hurler disease), or GBA (Gaucher disease) using AAV in wild type mice. We demonstrate stable integration of the IDS, IDUA and GBA donor cDNAs at the albumin locus, which resulted in liver-specific expression and secretion of these proteins into plasma. This led to a 4-fold (GBA), 10fold (IDUA) or 100-fold (IDS) increase in detectable enzymatic activity in the plasma, demonstrating that transgenes expressed from albumin are not only secreted from liver hepatocytes but are also enzymatically active. For IDS and IDUA, this correlated well with increased enzymatic activity and protein expression in the liver, and increased enzymatic activity was also detected in secondary tissues like the spleen. IDS, IDUA or GBA expression remained stable in mice for the duration of the study (1–2 months), suggesting that this process is well-tolerated. In summary, we have demonstrated proof of concept data using our in vivo protein replacement platform targeting the albumin locus to express different factors involved in lysosomal disease. Together our results support the further investigation of genome editing at the albumin locus as a novel method for in vivo protein replacement.
OF
using quantitative CSF flow MRI study and CSF lumbar pressure manometry to diagnose high intracranial pressure in MPS patients larger studies must be done to best determine which patients will respond positively to shunting.
RO
S36
UN
doi:10.1016/j.ymgme.2014.12.064
63 ZFN-mediated genome editing of albumin “safe harbor” in vivo results in supraphysiological levels of human IDS, IDUA and GBA in mice Russell DeKelver, Michelle Rohde, Susan Tom, Yolanda Santiago, Scott Sproul, Philip D. Gregory, Michael C. Holmes, Thomas Wechsler, Sangamo BioSciences, Richmond, CA, USA Current therapies for lysosomal diseases (LSD) include enzyme replacement strategies (ERT), substrate reduction therapies and allogeneic
doi:10.1016/j.ymgme.2014.12.065
64 Methods for cognitive assessment of children and adults with lysosomal diseases Kathleen A. Delaney, Elsa G. Shapiro, University of Minnesota, Minneapolis, MN, USA New treatments for diseases that affect brain require sensitive measures of disease progression and treatment outcome. Genetic diseases affecting the brain are associated with altered neurochemical, neurophysiological, and neurodevelopment processes that result in disease-specific neurocognitive and neurobehavioral phenotypes. The following approaches resulted from five years of a longitudinal study of the mucopolysaccharidoses but also apply to other lysosomal diseases. Measurement of neurocognitive growth and decline in brain structure and function require alterations in the methods of assessment due to chronological age and disease factors such as motor and sensory impairment and low cognitive functioning. Success in identifying disease-specific measures sensitive to disease progression