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O6-2 Cerebral PET and disability evaluation in patients with Niemann Pick disease Type C treated with miglustat
Oral presentations
Session 6: Parallel free papers session Queen’s Suite 1 October 2009, 16.30 18.00 O6-1 Loss-of-function mutations in the gene encoding the dopamine transporter, SLC6A3, cause Infantile Parkinsonism Dystonia (IPD) M.A. Kurian1,2 *, J. Zhen3 , S.-Y. Cheng3 , Y. Li3 , S.R. Mordekar4 , P. Jardine5 , N.V. Morgan1 , E. Meyer1 , L. Tee1 , S. Pasha1 , E. Wassmer2 , B. Assmann6 , S.J.R. Heales7 , P. Gissen1 , M.E.A. Reith3 , E.R. Maher1,8 . 1 Medical and Molecular Genetics, Birmingham University, Birmingham, UK; 2 Paediatric Neurology, Birmingham Children’s Hospital, Birmingham, UK; 3 Psychiatry and Pharmacology, New York University School of Medicine, New York, USA; 4 Paediatric Neurology, Sheffield Children’s Hospital, Sheffield, UK; 5 Paediatric Neurology, Bristol Children’s Hospital, Bristol, UK; 6 Paediatric Neurology, University Children’s Hospital, Dusseldorf, Germany; 7 Neurometabolic Unit, National Hospital, ¨ Queen Square & Department of Chemical Pathology, Great Ormond Street Hospital, UK; 8West Midlands Regional Genetics Service, Birmingham Women’s Hospital, Birmingham, UK Objective: IPD is a severe neurological syndrome that can mimic certain forms of cerebral palsy. In order to define this poorly understood condition, we undertook clinical and molecular genetic investigations to establish the key clinical features and identify the novel disease-causing gene. Methods: Children affected with IPD were clinically phenotyped. Autozygosity mapping studies were undertaken in consanguineous families to identify the causative gene. To determine the effects of the identified mutations, functional analysis of mutant proteins was performed. Results: Clinical presentation: Video footage illustrating affected children will be presented. Parkinsonism-dystonia heralded disease onset in early infancy, followed rapidly by the development of pyramidal tract features. There was no evidence of neuropsychiatric/behavioural disorders. CSF neurotransmitter studies revealed markedly elevated concentrations of HVA (with normal 5-HIAA levels). Molecular genetic investigation: Genetic linkage studies mapped a novel locus to chromosome 5p15.3. Homozygous missense SLC6A3 mutations (p.Leu368Gln and p.Pro395Leu) were identified. Functional studies demonstrated that both mutations severely reduced levels of mature (85 kDa) dopamine transporter (integral to dopamine reuptake) while differentially impacting dopamine binding affinity. Both mutations result in loss-of function of the dopamine transporter. Further SLC6A3 analysis in other IPD cases has identified more mutations (deletion/splice site mutations). Conclusions: We have identified the genetic basis of IPD which is linked to an inherited abnormality of dopamine transport. IPD is unique, as dopamine-related diseases in children are usually associated with defective dopamine synthesis. Genetic polymorphisms in SLC6A3 have also been linked to numerous neuropsychiatric disorders (particularly ADHD) as the knock-out mouse displays a hyperactive phenotype. However our study suggests that loss-of-function SLC6A3 mutations cause an movement disorder and not ADHD. SLC6A3 may thus be a candidate susceptibility gene for other movement disorders associated with parkinsonian or dystonic features. In memory of Robert Surtees, who was always a constant source of inspiration to his colleagues.
S13 O6-2 Cerebral PET and disability evaluation in patients with Niemann Pick disease Type C treated with miglustat M.S. Perez Poyato1 *, M. Pineda Marfa1 , M.A. Vilaseca2 , M.M. O’Callaghan Gordo1 , J. Macias3 , M.J. Coll3 . 1 Neurology Department, Sant Joan de Deu Hospital, Barcelona, Spain; 2 Biochemistry Department, Sant Joan de Deu Hospital, Barcelona, Spain; 3 Clinic Biochemistry Institute, Barcelona, Spain Background: Niemann Pick disease type C (NPC) is an autosomal recessive lipid-storage disorder with various phenotypic expressions depending on age of onset. Miglustat, a small iminosugar, is able to cross the blood brain barrier, and is thus a potential therapy for neurological diseases. A major problem in trials with miglustat in NPC has been the lack of quantifiable objective markers that could be predictive of clinical efficacy. Aims: We evaluated a cohort of patients from Spain and we aimed to establish the effect of miglustat on several markers of NPC severity. Methods: Our study includes 10 patients with biochemical and molecular diagnosis of NPC who are being followed in the last two or three years. Clinical forms: SI (n = 3), LI (n = 3), Juvenile (n = 4). All symptomatic patients received miglustat. We also included one asymptomatic patient without treatment, as protocol control. These patients applied a protocol including clinical analyses (neurological examination and modified disability scale) and cerebral PET studies. This protocol was usually applied at the baseline, six and twelve months and thereafter, annually. Results: In severe forms of the disease we have observed an increase on the disability evaluation and progressive affectation on cerebral PET when the patients start the treatment in advanced stages of the disease. Only a patient who showed a disability score higher, showed improvement in cerebral PET after a year of treatment. In juvenile forms a decrease in the disability score can be observed. PET scan has not showed progression in the juvenile forms of the disease. The asymptomatic patient has been useful as control in this series. Conclusions: The treatment efficacy is dependent on the clinical stage at treatment initiation. The PET study could be used as a quantitative and objective marker of treatment efficacy in early stages of the disease. Reference(s) [1] Patterson M, Vecchio D, Prady H et al. Miglustat for treatment of Niemmann Pick C disease: a randomised controlled study. Lancet Neurol 2007 (6): 765 772. [2] Paciorkowski AR, Westwell M, Ounpuu S et al. Motion analysis of a child with Niemann Pick disease type C treated with Miglustat. Mov Disord 2008 (23): 124 128. [3] Galanaud D, Tourbah A, Lehericy S et al. 24 month-treatment ` with miglustat of three patients with Niemann Pick disease type C: Follow up using brain spectroscopy. Molecular genetics and Metabolism 2008 (96): 55−58. [4] Iturriaga C, Pineda M, Fernandez-Valero EM et al. Niemann Pick ´ disease type C in Spain: clinical spectrum and development of a disability scale. J. Neurol Sci 2006; 249: 1−6. [5] Vanier MT, Millat G, Niemann Pick disease type C. Clin Genet 2003; 64: 269 281. [6] Chien YH, Lee NC, Tsai LK et al. Treatment of Niemann Pick disease type C in two children with miglustat: initial responses and maintenance of effects over 1 year. J Inherit Metab Dis 2007 (30): 826 833.
Session 6: Parallel free papers session Queen’s Suite 1 October 2009, 16.30 18.00 O6-1 Loss-of-function mutations in the gene encoding the dopamine transporter, SLC6A3, cause Infantile Parkinsonism Dystonia (IPD) M.A. Kurian1,2 *, J. Zhen3 , S.-Y. Cheng3 , Y. Li3 , S.R. Mordekar4 , P. Jardine5 , N.V. Morgan1 , E. Meyer1 , L. Tee1 , S. Pasha1 , E. Wassmer2 , B. Assmann6 , S.J.R. Heales7 , P. Gissen1 , M.E.A. Reith3 , E.R. Maher1,8 . 1 Medical and Molecular Genetics, Birmingham University, Birmingham, UK; 2 Paediatric Neurology, Birmingham Children’s Hospital, Birmingham, UK; 3 Psychiatry and Pharmacology, New York University School of Medicine, New York, USA; 4 Paediatric Neurology, Sheffield Children’s Hospital, Sheffield, UK; 5 Paediatric Neurology, Bristol Children’s Hospital, Bristol, UK; 6 Paediatric Neurology, University Children’s Hospital, Dusseldorf, Germany; 7 Neurometabolic Unit, National Hospital, ¨ Queen Square & Department of Chemical Pathology, Great Ormond Street Hospital, UK; 8West Midlands Regional Genetics Service, Birmingham Women’s Hospital, Birmingham, UK Objective: IPD is a severe neurological syndrome that can mimic certain forms of cerebral palsy. In order to define this poorly understood condition, we undertook clinical and molecular genetic investigations to establish the key clinical features and identify the novel disease-causing gene. Methods: Children affected with IPD were clinically phenotyped. Autozygosity mapping studies were undertaken in consanguineous families to identify the causative gene. To determine the effects of the identified mutations, functional analysis of mutant proteins was performed. Results: Clinical presentation: Video footage illustrating affected children will be presented. Parkinsonism-dystonia heralded disease onset in early infancy, followed rapidly by the development of pyramidal tract features. There was no evidence of neuropsychiatric/behavioural disorders. CSF neurotransmitter studies revealed markedly elevated concentrations of HVA (with normal 5-HIAA levels). Molecular genetic investigation: Genetic linkage studies mapped a novel locus to chromosome 5p15.3. Homozygous missense SLC6A3 mutations (p.Leu368Gln and p.Pro395Leu) were identified. Functional studies demonstrated that both mutations severely reduced levels of mature (85 kDa) dopamine transporter (integral to dopamine reuptake) while differentially impacting dopamine binding affinity. Both mutations result in loss-of function of the dopamine transporter. Further SLC6A3 analysis in other IPD cases has identified more mutations (deletion/splice site mutations). Conclusions: We have identified the genetic basis of IPD which is linked to an inherited abnormality of dopamine transport. IPD is unique, as dopamine-related diseases in children are usually associated with defective dopamine synthesis. Genetic polymorphisms in SLC6A3 have also been linked to numerous neuropsychiatric disorders (particularly ADHD) as the knock-out mouse displays a hyperactive phenotype. However our study suggests that loss-of-function SLC6A3 mutations cause an movement disorder and not ADHD. SLC6A3 may thus be a candidate susceptibility gene for other movement disorders associated with parkinsonian or dystonic features. In memory of Robert Surtees, who was always a constant source of inspiration to his colleagues.
S13 O6-2 Cerebral PET and disability evaluation in patients with Niemann Pick disease Type C treated with miglustat M.S. Perez Poyato1 *, M. Pineda Marfa1 , M.A. Vilaseca2 , M.M. O’Callaghan Gordo1 , J. Macias3 , M.J. Coll3 . 1 Neurology Department, Sant Joan de Deu Hospital, Barcelona, Spain; 2 Biochemistry Department, Sant Joan de Deu Hospital, Barcelona, Spain; 3 Clinic Biochemistry Institute, Barcelona, Spain Background: Niemann Pick disease type C (NPC) is an autosomal recessive lipid-storage disorder with various phenotypic expressions depending on age of onset. Miglustat, a small iminosugar, is able to cross the blood brain barrier, and is thus a potential therapy for neurological diseases. A major problem in trials with miglustat in NPC has been the lack of quantifiable objective markers that could be predictive of clinical efficacy. Aims: We evaluated a cohort of patients from Spain and we aimed to establish the effect of miglustat on several markers of NPC severity. Methods: Our study includes 10 patients with biochemical and molecular diagnosis of NPC who are being followed in the last two or three years. Clinical forms: SI (n = 3), LI (n = 3), Juvenile (n = 4). All symptomatic patients received miglustat. We also included one asymptomatic patient without treatment, as protocol control. These patients applied a protocol including clinical analyses (neurological examination and modified disability scale) and cerebral PET studies. This protocol was usually applied at the baseline, six and twelve months and thereafter, annually. Results: In severe forms of the disease we have observed an increase on the disability evaluation and progressive affectation on cerebral PET when the patients start the treatment in advanced stages of the disease. Only a patient who showed a disability score higher, showed improvement in cerebral PET after a year of treatment. In juvenile forms a decrease in the disability score can be observed. PET scan has not showed progression in the juvenile forms of the disease. The asymptomatic patient has been useful as control in this series. Conclusions: The treatment efficacy is dependent on the clinical stage at treatment initiation. The PET study could be used as a quantitative and objective marker of treatment efficacy in early stages of the disease. Reference(s) [1] Patterson M, Vecchio D, Prady H et al. Miglustat for treatment of Niemmann Pick C disease: a randomised controlled study. Lancet Neurol 2007 (6): 765 772. [2] Paciorkowski AR, Westwell M, Ounpuu S et al. Motion analysis of a child with Niemann Pick disease type C treated with Miglustat. Mov Disord 2008 (23): 124 128. [3] Galanaud D, Tourbah A, Lehericy S et al. 24 month-treatment ` with miglustat of three patients with Niemann Pick disease type C: Follow up using brain spectroscopy. Molecular genetics and Metabolism 2008 (96): 55−58. [4] Iturriaga C, Pineda M, Fernandez-Valero EM et al. Niemann Pick ´ disease type C in Spain: clinical spectrum and development of a disability scale. J. Neurol Sci 2006; 249: 1−6. [5] Vanier MT, Millat G, Niemann Pick disease type C. Clin Genet 2003; 64: 269 281. [6] Chien YH, Lee NC, Tsai LK et al. Treatment of Niemann Pick disease type C in two children with miglustat: initial responses and maintenance of effects over 1 year. J Inherit Metab Dis 2007 (30): 826 833.