- Email: [email protected]
Structural changes in the brain of patients with Gaucher disease
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Abstracts / Molecular Genetics and Metabolism 117 (2016) S14–S124
and respiratory, gross motor and feeding statuses. Patients received the bortezomib regimen due to HSAT [51,200-409,600] associated with rapid deterioration of cardiorespiratory function, feeding status, and motor function. Follow-up data available up to 204 weeks after bortezomib ITI demonstrates significant reduction in antibody titers [last titers 0-6400] associated with clinical improvements: improved respiratory and feeding status, reduction of LVMI and decreased Glc4 (n = 2). Two patients safely completed the regimen and are off all ITI medications with full recovery of immune function with continued ERT and maintain low titers. The remaining patients remain on the bortezomib protocol or low-dose immunosuppressive maintenance regimens. As immune responses limit the efficacy and cost-effectiveness of ERT, proteasome inhibitors may have novel applications—a major advance in the field of therapeutic proteins. doi:10.1016/j.ymgme.2015.12.199
42 Long term outcome of bone marrow transplantation for Hunter syndrome: A case report
Gaucher type 1 is the chronic, non-neuronopathic form of Gaucher Disease (GD). An association between mutations in the GBA1 gene and Parkinson disease has been recognized, in which those who are carriers of GD, and affected homozygotes, are predisposed to develop Parkinson disease. An alternative strategy to quantify gray matter morphometric abnormalities involves the use of surface-based methods, which produce measures of cortical thickness and cortical surface area. There are no magnetic resonance imaging (MRI) studies that tracked structural changes in patients with type 1 GD. This study investigated changes in deep cortical structures in type 1 GD patients. Using FreeSurfer software, we analyzed the volume from 8 regions of interest (right and left hippocampus, caudate, putamen and thalamus) in patients with GD (n = 26) and matched healthy controls (n = 28). Patients with GD presented increased left and right putaminal volume when compared to control patients (p b 0.005) and also depicted decreased left hippocampus volume (p = 0.023) and increased right caudate nucleus volume (p = 0.006). There was no significant difference between patients and control regarding thalamus, right hippocampus and left caudate. These results suggest that there are morphological changes in the brain of patients affected with type 1 Gaucher disease.
Lisa Berry, Laurie Bailey, T. Andrew Burrow, Connie Wehmeyer, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States
doi:10.1016/j.ymgme.2015.12.201
Hunter syndrome, or mucopolysaccaridosis type II (MPS II), is an Xlinked recessive, lysosomal disease caused by a deficiency of the enzyme iduronate 2 sulfatase. Current treatment for MPS II includes enzyme replacement therapy (ERT) with idursulfase. Although hematopoietic stem cell transplant (HSCT) was historically attempted and appeared to provide for improvements in peripheral manifestations, there has been no clear evidence for improvement or stabilization of neurologic outcome. Despite the limited evidence for benefit, and the risk associated with HSCT, this treatment is still offered for some with MPS II. We report here a case of a now 18 year old male with Hunter syndrome to describe the long term outcome of an individual who underwent HSCT. The patient, NG, was diagnosed with MPS II at 20 months of age. At that time, ERT was not clinically available and was not expected to cross the blood-brain barrier to stabilize neurological decline. The family opted to proceed with HSCT shortly after diagnosis. A matched donor was located and NG received his first transplant. A second transplant was required at 29 months of age due to loss of engraftment which resulted in 100% engraftment. Today, NG is ambulatory and has minimal pulmonary/cardiac disease. However, neurologically, he has cognitive impairment, aggressive behavior, incontinence and limited speech. NG shows no regression of skills at this time. The discussion of this case will highlight the issues faced by families when trying to determine the best course of treatment for their newly diagnosed children. We will present the long term clinical outcome for this individual from the cardiac, musculoskeletal, pulmonary, gastrointestinal, otolaryngological and neurological perspectives and will provide data on the modified phenotype of MPS II post transplant.
44 Molecular characterization and identification of novel mutations in the PPT1 gene causing neuronal ceroid lipofuscinosis-1 (NCL1) in children from India
doi:10.1016/j.ymgme.2015.12.200
43 Structural changes in the brain of patients with Gaucher disease Debora Bertholdoa,b, Filippo Vairoc, Ana Paula Vanzc, Raffael Massudac, Leonardo Vedolinc, Ida Schwartzc, aDAPI - Diagnóstico Avançado por Imagem, Curitiba, Brazil, bHospital de Clínicas da Universidade Federal do Paraná, Curitiba, Brazil, cHospital de Clinicas de Porto Alegre, Porto Alegre, Brazil
Riddhi A. Bhavsara, Jayesh J. Shetha, Mehul A. Mistria, Mahesh R. Kamateb, Frenny J. Shetha, aFRIGE's Institute of Human Genetics, Ahmedabad, India, bKLES PK Hospital, Belgaum, India The neuronal ceroid lipofuscinosis (NCL) are a group of rare heterogeneous neurodegenerative disorders with autosomal recessive inheritance. It occurs due to accumulation of fluorescent lipopigment mainly in the neurons. This leads to motor and intellectual impairment with seizures, with a very short life and impaired vision. These children do not survive beyond childhood. Though the disease is rare with cumulative incidence of all NCL to be 1:100,000, it poses a great mental, social and financial shock to the family. Neuronal ceroid lipofuscinosis-1 (NCL1) is also called an infantile neuronal ceroid lipofusionosis (INCL), occurs due to deficient activity of the enzyme palmitoyl-protein thioesterase 1 (PPT1) due to mutation in the PPT1 gene. This is the first report from India about the molecular pathology of NCL1 and its phenotypic correlation. Our study consists of 6 children presented at the age of 3 months – 7 years with impaired motor functions and neuroregression with seizures. Primary diagnosis was carried out by enzyme study of PPT1 from leucocytes followed by bidirectional Sanger sequencing of PPT1 gene. Study has identified seven pathogenic mutations: Five children carried homozygous missense mutations (V181M, P238L, C45R, N110S, and V236E) and one children was compound heterozygous (W186X and E178Nfs*13). Of seven mutations, four were found to be novel and confirmed to be pathogenic by Polyphen2, SIFT Provean and Mutation Taster online software program. While comparing genotype with phenotype, motor impairment, seizures and progressive vision loss was the most common among all genotype. Our study demonstrates heterogeneous molecular pathology in children with INCL comprises missense mutation being the most common. Study further adds that novel mutation seems to be more likely in these children from India. doi:10.1016/j.ymgme.2015.12.202
Abstracts / Molecular Genetics and Metabolism 117 (2016) S14–S124
and respiratory, gross motor and feeding statuses. Patients received the bortezomib regimen due to HSAT [51,200-409,600] associated with rapid deterioration of cardiorespiratory function, feeding status, and motor function. Follow-up data available up to 204 weeks after bortezomib ITI demonstrates significant reduction in antibody titers [last titers 0-6400] associated with clinical improvements: improved respiratory and feeding status, reduction of LVMI and decreased Glc4 (n = 2). Two patients safely completed the regimen and are off all ITI medications with full recovery of immune function with continued ERT and maintain low titers. The remaining patients remain on the bortezomib protocol or low-dose immunosuppressive maintenance regimens. As immune responses limit the efficacy and cost-effectiveness of ERT, proteasome inhibitors may have novel applications—a major advance in the field of therapeutic proteins. doi:10.1016/j.ymgme.2015.12.199
42 Long term outcome of bone marrow transplantation for Hunter syndrome: A case report
Gaucher type 1 is the chronic, non-neuronopathic form of Gaucher Disease (GD). An association between mutations in the GBA1 gene and Parkinson disease has been recognized, in which those who are carriers of GD, and affected homozygotes, are predisposed to develop Parkinson disease. An alternative strategy to quantify gray matter morphometric abnormalities involves the use of surface-based methods, which produce measures of cortical thickness and cortical surface area. There are no magnetic resonance imaging (MRI) studies that tracked structural changes in patients with type 1 GD. This study investigated changes in deep cortical structures in type 1 GD patients. Using FreeSurfer software, we analyzed the volume from 8 regions of interest (right and left hippocampus, caudate, putamen and thalamus) in patients with GD (n = 26) and matched healthy controls (n = 28). Patients with GD presented increased left and right putaminal volume when compared to control patients (p b 0.005) and also depicted decreased left hippocampus volume (p = 0.023) and increased right caudate nucleus volume (p = 0.006). There was no significant difference between patients and control regarding thalamus, right hippocampus and left caudate. These results suggest that there are morphological changes in the brain of patients affected with type 1 Gaucher disease.
Lisa Berry, Laurie Bailey, T. Andrew Burrow, Connie Wehmeyer, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States
doi:10.1016/j.ymgme.2015.12.201
Hunter syndrome, or mucopolysaccaridosis type II (MPS II), is an Xlinked recessive, lysosomal disease caused by a deficiency of the enzyme iduronate 2 sulfatase. Current treatment for MPS II includes enzyme replacement therapy (ERT) with idursulfase. Although hematopoietic stem cell transplant (HSCT) was historically attempted and appeared to provide for improvements in peripheral manifestations, there has been no clear evidence for improvement or stabilization of neurologic outcome. Despite the limited evidence for benefit, and the risk associated with HSCT, this treatment is still offered for some with MPS II. We report here a case of a now 18 year old male with Hunter syndrome to describe the long term outcome of an individual who underwent HSCT. The patient, NG, was diagnosed with MPS II at 20 months of age. At that time, ERT was not clinically available and was not expected to cross the blood-brain barrier to stabilize neurological decline. The family opted to proceed with HSCT shortly after diagnosis. A matched donor was located and NG received his first transplant. A second transplant was required at 29 months of age due to loss of engraftment which resulted in 100% engraftment. Today, NG is ambulatory and has minimal pulmonary/cardiac disease. However, neurologically, he has cognitive impairment, aggressive behavior, incontinence and limited speech. NG shows no regression of skills at this time. The discussion of this case will highlight the issues faced by families when trying to determine the best course of treatment for their newly diagnosed children. We will present the long term clinical outcome for this individual from the cardiac, musculoskeletal, pulmonary, gastrointestinal, otolaryngological and neurological perspectives and will provide data on the modified phenotype of MPS II post transplant.
44 Molecular characterization and identification of novel mutations in the PPT1 gene causing neuronal ceroid lipofuscinosis-1 (NCL1) in children from India
doi:10.1016/j.ymgme.2015.12.200
43 Structural changes in the brain of patients with Gaucher disease Debora Bertholdoa,b, Filippo Vairoc, Ana Paula Vanzc, Raffael Massudac, Leonardo Vedolinc, Ida Schwartzc, aDAPI - Diagnóstico Avançado por Imagem, Curitiba, Brazil, bHospital de Clínicas da Universidade Federal do Paraná, Curitiba, Brazil, cHospital de Clinicas de Porto Alegre, Porto Alegre, Brazil
Riddhi A. Bhavsara, Jayesh J. Shetha, Mehul A. Mistria, Mahesh R. Kamateb, Frenny J. Shetha, aFRIGE's Institute of Human Genetics, Ahmedabad, India, bKLES PK Hospital, Belgaum, India The neuronal ceroid lipofuscinosis (NCL) are a group of rare heterogeneous neurodegenerative disorders with autosomal recessive inheritance. It occurs due to accumulation of fluorescent lipopigment mainly in the neurons. This leads to motor and intellectual impairment with seizures, with a very short life and impaired vision. These children do not survive beyond childhood. Though the disease is rare with cumulative incidence of all NCL to be 1:100,000, it poses a great mental, social and financial shock to the family. Neuronal ceroid lipofuscinosis-1 (NCL1) is also called an infantile neuronal ceroid lipofusionosis (INCL), occurs due to deficient activity of the enzyme palmitoyl-protein thioesterase 1 (PPT1) due to mutation in the PPT1 gene. This is the first report from India about the molecular pathology of NCL1 and its phenotypic correlation. Our study consists of 6 children presented at the age of 3 months – 7 years with impaired motor functions and neuroregression with seizures. Primary diagnosis was carried out by enzyme study of PPT1 from leucocytes followed by bidirectional Sanger sequencing of PPT1 gene. Study has identified seven pathogenic mutations: Five children carried homozygous missense mutations (V181M, P238L, C45R, N110S, and V236E) and one children was compound heterozygous (W186X and E178Nfs*13). Of seven mutations, four were found to be novel and confirmed to be pathogenic by Polyphen2, SIFT Provean and Mutation Taster online software program. While comparing genotype with phenotype, motor impairment, seizures and progressive vision loss was the most common among all genotype. Our study demonstrates heterogeneous molecular pathology in children with INCL comprises missense mutation being the most common. Study further adds that novel mutation seems to be more likely in these children from India. doi:10.1016/j.ymgme.2015.12.202