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A study of intrathecal enzyme replacement for cognitive decline in mucopolysaccharidosis I
Abstracts
37 New insights from Glycoproteinoses Clinics 2012: Two days, six rare diseases, thirty patients Sara Catheya, Laura Pollarda, Lucia Horowitza, Nicholas Pietrisb, Carlos Salinasb, Ronald Teedc, Tim Wooda, Jules Leroya, aGreenwood Genetic Center, N. Charleston, SC, USA, bMedical Univeristy of South Carolina, Charleston, SC, USA, cChildrens Eye Specialists, Ladson, SC, USA Background: Longitudinal studies of the glycoproteinoses have been undertaken to detail the natural course of these rare diseases, assess genotype–phenotype correlations, and establish clinical and laboratory databases. The Greenwood Genetic Center hosted Glycoproteinoses Clinics in July, 2012 in conjunction with the Third International Conference for Glycoproteinoses in Charleston, South Carolina. Methods: Every patient attending the multi-disciplinary clinic was evaluated by a geneticist, cardiologist, dentist, neurologist, ophthalmologist, orthopedist, and psychologist. All patients had electrocardiogram, transthoracic echocardiogram, and cognitive testing (KBITII or DAYC). Adaptive functioning measures (Vineland Adaptive Behavior Scale) and Parent Stress Index were completed for most patients. Blood, urine, and fibroblasts were collected from patients and parents. Diagnoses were confirmed with biochemical studies, and causative genes were sequenced. Results: Six different glycoproteinoses disorders were represented in this cohort of thirty patients, ages 2–40 years: alpha-mannosidosis (7), mucolipidosis (ML) II (2), ML III (17, including four patients best categorized as having intermediate ML II/III), fucosidosis (1), galactosialidosis (1), and aspartylglucosaminuria (2). Analysis of the extensive data collected is ongoing but has already yielded new insights for each condition. For example, findings in patients with alphamannosidosis include normocephaly 7/7, retinal vasculature tortuosity 6/7, mandibular torus or buccal exostosis 4/7, and tooth discoloration 5/ 7. For the first time, GNTPAB genotype/cardiac phenotype correlations are made. Novel mutations are reported for FUCA1, MAN2B1, AGA, and GNPTAB genes. Conclusions: Glycoproteinoses Clinics 2012 yielded extensive natural history data and rare laboratory samples. Clinical, biochemical, and molecular data will be presented. doi:10.1016/j.ymgme.2012.11.051
38 A study of intrathecal enzyme replacement for cognitive decline in mucopolysaccharidosis I
S29
month open-label continuation. Eleven subjects have enrolled and seven have received treatment (some after a 12 month nontreatment control period). Adverse events possibly related to IT ERT include low back pain, neck stiffness, headache, and transient blurry vision. There have been no serious adverse events related to treatment. Further study is needed to determine whether IT ERT can be used to treat cognitive decline in MPS I patients who do not qualify for and/or are unable to have hematopoietic stem cell transplantation. doi:10.1016/j.ymgme.2012.11.052
39 Augmenting glucocerebrosidase activity in the CNS as a therapeutic strategy for Gaucher-related synucleinopathies Seng Cheng, Pablo Sardi, Lamya Shihabuddin, Genzyme, a Sanofi Company, Framingham, MA, USA Mutations of GBA1, the gene encoding glucocerebrosidase, represent a common genetic risk factor for developing the synucleinopathies Parkinson's disease (PD) and dementia with Lewy bodies (DLB). PD patients with or without GBA1 mutations also exhibit lower enzymatic levels of glucocerebrosidase in the central nervous system (CNS), suggesting a possible link between the enzyme and the development of the disease. To probe this link further, we evaluated the efficacy of augmenting glucocerebrosidase activity in the CNS of a mouse model of Gaucher-related synucleinopathy (Gba1D409V/D409V) and a transgenic mouse overexpressing A53T alpha-synuclein. Adeno-associated virus-mediated expression of glucocerebrosidase in the CNSs of symptomatic Gba1D409V/D409V mice completely corrected the aberrant accumulation of the toxic lipid glucosylsphingosine and reduced the levels of ubiquitin and proteinase-K-resistant alpha-synuclein aggregates. Importantly, hippocampal expression of glucocerebrosidase in Gba1D409V/D409V mice (starting at 4 or 12 months old) also reversed their cognitive impairment when examined using the novel object recognition test. Overexpression of glucocerebrosidase in the CNSs of A53T alpha-synuclein mice reduced the levels of soluble alphasynuclein, suggesting that this glycosidase can modulate the development of alpha-synucleinopathies. Hence, increasing glucocerebrosidase activity in the CNS represents a potential therapeutic strategy for GBA1related and non-GBA1-associated synucleinopathies. doi:10.1016/j.ymgme.2012.11.053
Agnes Chena, Patricia Dicksona, Elsa Shapirob, Leonor Rovaia, Shih-hsin Kana, aLos Angeles Biomedical Research Institute at Harbor-UCLA, Torrance, CA, USA, bUniversity of Minnesota, Minneapolis, MN, USA
40 Long-term follow-up results in patients with classic infantile Pompe disease receiving enzyme therapy since newborn
Patients with attenuated MPS I have been found to suffer from progressive decline in memory and intelligence which is inadequately treated with intravenous enzyme replacement therapy (ERT). This ongoing study investigates intrathecal (IT) ERT with recombinant human alpha-L iduronidase (formulated as laronidase) as a treatment for cognitive decline. This study is a twenty-four month open label prospective randomized study in 16 MPS I patients age 6 or older with intellectual impairment or functional decrease over time. Subjects receive baseline neuropsychological, clinical, radiological, and biochemical evaluations and then are monitored for change in these parameters during first monthly, then quarterly IT ERT. The study randomizes subjects to a treatment and a control group for 12 months, and then all subjects receive treatment on a 12-
Yin-Hsiu Chiena, Wuh-Liang Hwua, Ni-Chung Leea, Chun-An Chena, Fuu-Jen Tsaib, Wen-Hui Tsaic, Hsiang-Ju Huanga, Wei-Chung Hsua, Tzu-Hsun Tsaia, Jeng-Yi Shieha, aNational Taiwan University Hospital, Taipei, Taiwan, Taiwan, bCollage of Chinese Medicine, Taichung, Taiwan, c Chi-Mei Foundation Hospital, Tainai, Taiwan, (d) Chen Hsin Hospital, Taipei, Taiwan Background: Newborn screening for Pompe disease has been started in Taiwan since 2005. Patients affected by infantile-onset Pompe disease (IOPD) were diagnosed and treated by enzyme replacement therapy (ERT) during their first month of life. We have reported that newborn screening improves the survival of IOPD, and now we present long-term follow-up results of these patients.
37 New insights from Glycoproteinoses Clinics 2012: Two days, six rare diseases, thirty patients Sara Catheya, Laura Pollarda, Lucia Horowitza, Nicholas Pietrisb, Carlos Salinasb, Ronald Teedc, Tim Wooda, Jules Leroya, aGreenwood Genetic Center, N. Charleston, SC, USA, bMedical Univeristy of South Carolina, Charleston, SC, USA, cChildrens Eye Specialists, Ladson, SC, USA Background: Longitudinal studies of the glycoproteinoses have been undertaken to detail the natural course of these rare diseases, assess genotype–phenotype correlations, and establish clinical and laboratory databases. The Greenwood Genetic Center hosted Glycoproteinoses Clinics in July, 2012 in conjunction with the Third International Conference for Glycoproteinoses in Charleston, South Carolina. Methods: Every patient attending the multi-disciplinary clinic was evaluated by a geneticist, cardiologist, dentist, neurologist, ophthalmologist, orthopedist, and psychologist. All patients had electrocardiogram, transthoracic echocardiogram, and cognitive testing (KBITII or DAYC). Adaptive functioning measures (Vineland Adaptive Behavior Scale) and Parent Stress Index were completed for most patients. Blood, urine, and fibroblasts were collected from patients and parents. Diagnoses were confirmed with biochemical studies, and causative genes were sequenced. Results: Six different glycoproteinoses disorders were represented in this cohort of thirty patients, ages 2–40 years: alpha-mannosidosis (7), mucolipidosis (ML) II (2), ML III (17, including four patients best categorized as having intermediate ML II/III), fucosidosis (1), galactosialidosis (1), and aspartylglucosaminuria (2). Analysis of the extensive data collected is ongoing but has already yielded new insights for each condition. For example, findings in patients with alphamannosidosis include normocephaly 7/7, retinal vasculature tortuosity 6/7, mandibular torus or buccal exostosis 4/7, and tooth discoloration 5/ 7. For the first time, GNTPAB genotype/cardiac phenotype correlations are made. Novel mutations are reported for FUCA1, MAN2B1, AGA, and GNPTAB genes. Conclusions: Glycoproteinoses Clinics 2012 yielded extensive natural history data and rare laboratory samples. Clinical, biochemical, and molecular data will be presented. doi:10.1016/j.ymgme.2012.11.051
38 A study of intrathecal enzyme replacement for cognitive decline in mucopolysaccharidosis I
S29
month open-label continuation. Eleven subjects have enrolled and seven have received treatment (some after a 12 month nontreatment control period). Adverse events possibly related to IT ERT include low back pain, neck stiffness, headache, and transient blurry vision. There have been no serious adverse events related to treatment. Further study is needed to determine whether IT ERT can be used to treat cognitive decline in MPS I patients who do not qualify for and/or are unable to have hematopoietic stem cell transplantation. doi:10.1016/j.ymgme.2012.11.052
39 Augmenting glucocerebrosidase activity in the CNS as a therapeutic strategy for Gaucher-related synucleinopathies Seng Cheng, Pablo Sardi, Lamya Shihabuddin, Genzyme, a Sanofi Company, Framingham, MA, USA Mutations of GBA1, the gene encoding glucocerebrosidase, represent a common genetic risk factor for developing the synucleinopathies Parkinson's disease (PD) and dementia with Lewy bodies (DLB). PD patients with or without GBA1 mutations also exhibit lower enzymatic levels of glucocerebrosidase in the central nervous system (CNS), suggesting a possible link between the enzyme and the development of the disease. To probe this link further, we evaluated the efficacy of augmenting glucocerebrosidase activity in the CNS of a mouse model of Gaucher-related synucleinopathy (Gba1D409V/D409V) and a transgenic mouse overexpressing A53T alpha-synuclein. Adeno-associated virus-mediated expression of glucocerebrosidase in the CNSs of symptomatic Gba1D409V/D409V mice completely corrected the aberrant accumulation of the toxic lipid glucosylsphingosine and reduced the levels of ubiquitin and proteinase-K-resistant alpha-synuclein aggregates. Importantly, hippocampal expression of glucocerebrosidase in Gba1D409V/D409V mice (starting at 4 or 12 months old) also reversed their cognitive impairment when examined using the novel object recognition test. Overexpression of glucocerebrosidase in the CNSs of A53T alpha-synuclein mice reduced the levels of soluble alphasynuclein, suggesting that this glycosidase can modulate the development of alpha-synucleinopathies. Hence, increasing glucocerebrosidase activity in the CNS represents a potential therapeutic strategy for GBA1related and non-GBA1-associated synucleinopathies. doi:10.1016/j.ymgme.2012.11.053
Agnes Chena, Patricia Dicksona, Elsa Shapirob, Leonor Rovaia, Shih-hsin Kana, aLos Angeles Biomedical Research Institute at Harbor-UCLA, Torrance, CA, USA, bUniversity of Minnesota, Minneapolis, MN, USA
40 Long-term follow-up results in patients with classic infantile Pompe disease receiving enzyme therapy since newborn
Patients with attenuated MPS I have been found to suffer from progressive decline in memory and intelligence which is inadequately treated with intravenous enzyme replacement therapy (ERT). This ongoing study investigates intrathecal (IT) ERT with recombinant human alpha-L iduronidase (formulated as laronidase) as a treatment for cognitive decline. This study is a twenty-four month open label prospective randomized study in 16 MPS I patients age 6 or older with intellectual impairment or functional decrease over time. Subjects receive baseline neuropsychological, clinical, radiological, and biochemical evaluations and then are monitored for change in these parameters during first monthly, then quarterly IT ERT. The study randomizes subjects to a treatment and a control group for 12 months, and then all subjects receive treatment on a 12-
Yin-Hsiu Chiena, Wuh-Liang Hwua, Ni-Chung Leea, Chun-An Chena, Fuu-Jen Tsaib, Wen-Hui Tsaic, Hsiang-Ju Huanga, Wei-Chung Hsua, Tzu-Hsun Tsaia, Jeng-Yi Shieha, aNational Taiwan University Hospital, Taipei, Taiwan, Taiwan, bCollage of Chinese Medicine, Taichung, Taiwan, c Chi-Mei Foundation Hospital, Tainai, Taiwan, (d) Chen Hsin Hospital, Taipei, Taiwan Background: Newborn screening for Pompe disease has been started in Taiwan since 2005. Patients affected by infantile-onset Pompe disease (IOPD) were diagnosed and treated by enzyme replacement therapy (ERT) during their first month of life. We have reported that newborn screening improves the survival of IOPD, and now we present long-term follow-up results of these patients.