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A novel mutation in guanidinoacetate methyltransferase (GAMT) deficiency in two patients associated with epilepsy, developmental delay, hyperactivity, autistic behavior
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 2 1 ( 2 0 1 7 ) e 1 2 3 ee 1 4 0
vermis relative diameter (MVRD) and volume] of children with PMM2-CDG and sex- and age-matched controls, and to determine the rate of progression of cerebellar atrophy at different ages. Ethical permission was obtained from our Research & Ethics Committee. Statistical analysis was performed using SPSS V.22.0. Results: Fifty MRI studies of 33 PMM2-CDG patients were used for 2D evaluation, and 19 MRI studies were available for volumetric analysis. Results from linear regression model showed that patients have significantly lower MVRD and cerebellar volume compared to controls (p < 0.001 and p < 0.001 respectively). There was a significant negative correlation between age and MVRD for patients (p ¼ 0.014). The rate of cerebellar atrophy measured by the loss of MVRD and cerebellar volume per year was higher at early ages (r ¼ 0.578, p ¼ 0.012 and r ¼ 0.323, p ¼ 0.48 respectively), particularly in patients under 11 years (p ¼ 0.004). There was a significant positive correlation between MVRD and cerebellar volume in PMM2-CDG patients (r ¼ 0.669, p ¼ 0.001). Conclusion: To our knowledge, this is the first study in PMM2-CDG patients in which a volumetric method is applied to evaluate the cerebellar atrophy. Our study quantifies a progression of cerebellar atrophy, particularly during the first decade of life, and suggests a simple and reliable measure, the MVRD, to monitor cerebellar atrophy. Quantitative measurement of MVRD and cerebellar volume are essential for correlation with phenotype and outcome, as well as natural follow-up. The description of the natural radiological evolution of the cerebellum in PMM2-CDG and the use of radiologic quantitative methods are essential to quantify cerebellum changes in case of potential therapies
http://dx.doi.org/10.1016/j.ejpn.2017.04.1004 P2-89 A novel mutation in guanidinoacetate methyltransferase (GAMT) deficiency in two patients associated with epilepsy, developmental delay, hyperactivity, autistic behavior Halil Ibrahim Aydin, F. Mujgan Sonmez. Baskent University, Medical Faculty, Dept of Pediatric Metabolism, Ankara, Turkey Objective: Cerebral creatine deficiency syndromes (CDS) cover two autosomal recessive disorders in creatine synthesis and X-linked creatine transporter defect. In all CDS, creatine deficiency in body fluids, muscle and brain are common. Creatine synthesis defects are glycine aminotransferase (AGAT) and guanidinoacetate methyltransferase (GAMT) deficiencies. GAMT deficiency results in accumulation of guanidinoacetate, an intermediary metabolite in creatine synthesis, which is known to be neurotoxic and epileptogenic. GAMT deficiency is characterized with epilepsy, movement disorders and learning disabilities. A number of different mutations in GAMT gene are known to cause GAMT deficiency. Methods: We here present two children (10 years-oldmale and 9 years-old female) with GAMT deficiency who were followed up in another health care center with the diagnosis of autism and hyperactivity. They are cousins and both from firstdegree cousin marriage. Our patients presented with developmental delay, have epilepsy and speech impairment without movement disorders. Results: The levels of creatine in both were found between 0.01 mg/dl and 0.2 mg/dl on numerous occasions, but had not been recognized as a clue for presumptive diagnosis of creatine synthesis defects. Brain magnetic resonance spectroscopy showed the absence of creatine peak in basal ganglia and white matter. We identified a novel homozygous mutation (1. exon p. Cys*, c.C48A) in the index patient. The parents were found heterogeneous for his mutation. This mutation was a nonsense
e125
mutation leading to stop the synthesis of the protein in GAMT gene. Conclusion: The creatine synthesis defects (AGAT and GAMT) are treatable disorders, but they are underdiagnosed. The serum creatinine level should be carefully checked for the diagnosis of creatine synthesis defects in all children with developmental e- delay, epilepsy and autistic features.
http://dx.doi.org/10.1016/j.ejpn.2017.04.1005 P2-90 Epilepsy during the course of MPS: Report of 115 patients Gasperini Serena, Sala Elisa, Galimberti Cinzia, Grioni Daniele, Parini Rossella. Paediatric Department Metabolic Disease Unit, MBBM Foundation, Monza (MB), Italy Objective: This study aims to assess the clinical features of epilepsy in MPS patients. Methods: Among all MPS patients followed in our center we selected the ones presenting epileptic seizures. Patients data were retrospectively collected from medical records and physical examination. Results: We included 115 patients. 29/ 115 (25%) patients developed epilepsy: 5/26 with MPS I (19.2%), 9/26 with MPS II (34.6%) and 15/28 with MPS III (53,6%). Only patients with MPS I, II and III presented epileptic seizures, contrarily no patients with MPS IV, VI e VII had epilepsy. The mean age at onset of seizures was 12 years in MPS I, 10.4 years in MPS II and 10.5 years in MPS III patients respectively. At the onset, most patients presented subtle focal seizures, which could evolve into generalized seizures during the course of MPS. Usually, MPS patients with epileptic seizures were responsive to low dosage monotherapy with antiepileptic drugs. Just few patients needed polytherapy, mainly the ones who entered the final stage of disease. Conclusion: There are only few studies exploring clinical features of epilepsy in MPS patients. Our results suggest that epilepsy occurs frequently in MPS I, II and III patients at mean age ranging between 10.4 and 12 year. The onset of epileptic seizures is considerably lower than reported in previous studies 1. The majority of cases responded to monotherapy. The aim of our study was to increase the knowledge of epilepsy in MPS patients because underdiagnosed and undertreated seizures could lead faster to neurological deterioration.
http://dx.doi.org/10.1016/j.ejpn.2017.04.1006 P2-91 Long-term neurodevelopmental outcome of patients with Mucopolysaccharidosis-1H (MPS-1H) following hematopoietic stem cell transplantation (HSCT) H. Hartmann, J. Pru¨fe, S. Illsinger, A.M. Das, T. Lu¨cke, L. Grigull. Clinic for Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany Objective: HSCT is considered standard of care for MPS-1H diagnosed in infancy. In contrast to enzyme replacement therapy, it has the potential to deliver the deficient enzyme a-L-iduronidase to the CNS. We assessed neurodevelopmental outcome more than 10 y after HSCT in a cohort of patients, in whom we had previously shown developmental progress but ongoing mild to moderate psychomotor retardation on short term follow-up (Lu¨cke et al. Dev Med Child Neurol (2007)). Methods: The 5 patients (4 f, 1m) underwent HSCT at a median age of 1.91 y (0.82e2.99) and were studied after a median follow-up time of 11.51 y (10.02e13.64). Besides physical and neurological examination, patients underwent quantitative neuropsychological assessment with either
vermis relative diameter (MVRD) and volume] of children with PMM2-CDG and sex- and age-matched controls, and to determine the rate of progression of cerebellar atrophy at different ages. Ethical permission was obtained from our Research & Ethics Committee. Statistical analysis was performed using SPSS V.22.0. Results: Fifty MRI studies of 33 PMM2-CDG patients were used for 2D evaluation, and 19 MRI studies were available for volumetric analysis. Results from linear regression model showed that patients have significantly lower MVRD and cerebellar volume compared to controls (p < 0.001 and p < 0.001 respectively). There was a significant negative correlation between age and MVRD for patients (p ¼ 0.014). The rate of cerebellar atrophy measured by the loss of MVRD and cerebellar volume per year was higher at early ages (r ¼ 0.578, p ¼ 0.012 and r ¼ 0.323, p ¼ 0.48 respectively), particularly in patients under 11 years (p ¼ 0.004). There was a significant positive correlation between MVRD and cerebellar volume in PMM2-CDG patients (r ¼ 0.669, p ¼ 0.001). Conclusion: To our knowledge, this is the first study in PMM2-CDG patients in which a volumetric method is applied to evaluate the cerebellar atrophy. Our study quantifies a progression of cerebellar atrophy, particularly during the first decade of life, and suggests a simple and reliable measure, the MVRD, to monitor cerebellar atrophy. Quantitative measurement of MVRD and cerebellar volume are essential for correlation with phenotype and outcome, as well as natural follow-up. The description of the natural radiological evolution of the cerebellum in PMM2-CDG and the use of radiologic quantitative methods are essential to quantify cerebellum changes in case of potential therapies
http://dx.doi.org/10.1016/j.ejpn.2017.04.1004 P2-89 A novel mutation in guanidinoacetate methyltransferase (GAMT) deficiency in two patients associated with epilepsy, developmental delay, hyperactivity, autistic behavior Halil Ibrahim Aydin, F. Mujgan Sonmez. Baskent University, Medical Faculty, Dept of Pediatric Metabolism, Ankara, Turkey Objective: Cerebral creatine deficiency syndromes (CDS) cover two autosomal recessive disorders in creatine synthesis and X-linked creatine transporter defect. In all CDS, creatine deficiency in body fluids, muscle and brain are common. Creatine synthesis defects are glycine aminotransferase (AGAT) and guanidinoacetate methyltransferase (GAMT) deficiencies. GAMT deficiency results in accumulation of guanidinoacetate, an intermediary metabolite in creatine synthesis, which is known to be neurotoxic and epileptogenic. GAMT deficiency is characterized with epilepsy, movement disorders and learning disabilities. A number of different mutations in GAMT gene are known to cause GAMT deficiency. Methods: We here present two children (10 years-oldmale and 9 years-old female) with GAMT deficiency who were followed up in another health care center with the diagnosis of autism and hyperactivity. They are cousins and both from firstdegree cousin marriage. Our patients presented with developmental delay, have epilepsy and speech impairment without movement disorders. Results: The levels of creatine in both were found between 0.01 mg/dl and 0.2 mg/dl on numerous occasions, but had not been recognized as a clue for presumptive diagnosis of creatine synthesis defects. Brain magnetic resonance spectroscopy showed the absence of creatine peak in basal ganglia and white matter. We identified a novel homozygous mutation (1. exon p. Cys*, c.C48A) in the index patient. The parents were found heterogeneous for his mutation. This mutation was a nonsense
e125
mutation leading to stop the synthesis of the protein in GAMT gene. Conclusion: The creatine synthesis defects (AGAT and GAMT) are treatable disorders, but they are underdiagnosed. The serum creatinine level should be carefully checked for the diagnosis of creatine synthesis defects in all children with developmental e- delay, epilepsy and autistic features.
http://dx.doi.org/10.1016/j.ejpn.2017.04.1005 P2-90 Epilepsy during the course of MPS: Report of 115 patients Gasperini Serena, Sala Elisa, Galimberti Cinzia, Grioni Daniele, Parini Rossella. Paediatric Department Metabolic Disease Unit, MBBM Foundation, Monza (MB), Italy Objective: This study aims to assess the clinical features of epilepsy in MPS patients. Methods: Among all MPS patients followed in our center we selected the ones presenting epileptic seizures. Patients data were retrospectively collected from medical records and physical examination. Results: We included 115 patients. 29/ 115 (25%) patients developed epilepsy: 5/26 with MPS I (19.2%), 9/26 with MPS II (34.6%) and 15/28 with MPS III (53,6%). Only patients with MPS I, II and III presented epileptic seizures, contrarily no patients with MPS IV, VI e VII had epilepsy. The mean age at onset of seizures was 12 years in MPS I, 10.4 years in MPS II and 10.5 years in MPS III patients respectively. At the onset, most patients presented subtle focal seizures, which could evolve into generalized seizures during the course of MPS. Usually, MPS patients with epileptic seizures were responsive to low dosage monotherapy with antiepileptic drugs. Just few patients needed polytherapy, mainly the ones who entered the final stage of disease. Conclusion: There are only few studies exploring clinical features of epilepsy in MPS patients. Our results suggest that epilepsy occurs frequently in MPS I, II and III patients at mean age ranging between 10.4 and 12 year. The onset of epileptic seizures is considerably lower than reported in previous studies 1. The majority of cases responded to monotherapy. The aim of our study was to increase the knowledge of epilepsy in MPS patients because underdiagnosed and undertreated seizures could lead faster to neurological deterioration.
http://dx.doi.org/10.1016/j.ejpn.2017.04.1006 P2-91 Long-term neurodevelopmental outcome of patients with Mucopolysaccharidosis-1H (MPS-1H) following hematopoietic stem cell transplantation (HSCT) H. Hartmann, J. Pru¨fe, S. Illsinger, A.M. Das, T. Lu¨cke, L. Grigull. Clinic for Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany Objective: HSCT is considered standard of care for MPS-1H diagnosed in infancy. In contrast to enzyme replacement therapy, it has the potential to deliver the deficient enzyme a-L-iduronidase to the CNS. We assessed neurodevelopmental outcome more than 10 y after HSCT in a cohort of patients, in whom we had previously shown developmental progress but ongoing mild to moderate psychomotor retardation on short term follow-up (Lu¨cke et al. Dev Med Child Neurol (2007)). Methods: The 5 patients (4 f, 1m) underwent HSCT at a median age of 1.91 y (0.82e2.99) and were studied after a median follow-up time of 11.51 y (10.02e13.64). Besides physical and neurological examination, patients underwent quantitative neuropsychological assessment with either