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P308 Observation of NO pathway in homocystinuria and phenylketonuria (PKU)
Posters nervous system. This was completed by quantifying glial activation in multiple brain regions for GFAP and F4/80 immunoreactivity in double knockout mice (n = 4), Cln3 −/− mice (n = 3), and age-matched controls (n = 4) at 2 months and 6 months of age. Results: Presymptomatic Cln3 −/− mice exhibit significant upregulation of astrocytic and microglial markers. The glial activation profile in presymptomatic double knockout mice are phenotypically similar to that of control animals. Functional assessment revealed that double knockout mice performed better on an accelerating rotarod than Cln3 −/− mice. Conclusion: These data provide early evidence for the role of the neuroinflammatory response in Batten disease. An immunomodulatory trial is now underway to recapitulate this effect in Cln3 −/− mice. Reference(s) [1] Mitchison HM, Lim MJ, Cooper JD. Brain Pathol. 2004; 14: 86−96. [2] Lim MJ, Beake J, Bible E, et al., Neuropathol. Appl. Neurobiol. In Press
P308 Observation of NO pathway in homocystinuria and phenylketonuria (PKU) N.K. Kanzelmeyer1 , D. Tsikas2 , H. Hartmann1 , S. Illsinger1 , 1 *. 1 Department of Paediatrics, Hannover A.M. Das1 , T. Lucke ¨ Medical School, Hannover, Germany; 2 Clinical Pharmacology, Hannover Medical School, Hannover, Germany Background: ADMA, an endogenous inhibitor of NO-synthase, has recently been identified as a cardiovascular risk factor. We studied the L-arginine NO-pathway in children with homocystinuria − a disease with well known cardiovascular risk − and with phenylketonurie (PKU). PKU, a disease with suspicious but not proven cardiovascular risk, was studied because tetrahydrobiopterin (BH4) is involved in both, phenylalanine degradation and NO-synthesis. Methods: ADMA in plasma and urine was determined by gas chromatography-tandem mass spectrometry (GC-MSMS). Nitrate and nitrite in plasma and urine were measured simultaneously by GC-MS. Results: Plasma ADMA levels in patients with homocystinuria were significantly higher than in healthy age-matched controls (660±158 versus 475±77 nmol/L, p = 0.035, n = 6). In patients with PKU ADMA plasma levels were significantly lower compared to age matched healthy controls (512±136 versus 585±125 nmol/L, p = 0.009; n = 52). Neither in the PKU group nor in two additional patients studied during the BH4 test, a clear correlation between ADMA and phenylalanine levels in plasma were found. Conclusion: Metabolism/elimination of ADMA is altered in children suffering from homocystinuria or PKU. However, delineation of the role of ADMA in these diseases demands further investigations. P309 Neuropsychiatry in paediatric Wilson’s disease − need for surveillance and management S. Mehta1,2,3 *, P. Hindley1,2,3 , A. Dhawan1 , M. Samuel1 , T. Hedderly1,2 . 1 Paediatric Neurosciences, King’s College Hospital and KHP, UK; 2 Paediatric Neurosciences, Evelina Children’s Hospital, GSTT, UK; 3 Institute of Psychiatry, South London and Maudsley, UK Objective: Wilson’s disease (WD) is an inherited disorder of copper metabolism known to present with hepatological, haematological and neuropsychiatric symptoms. There is little known about psychiatric symptoms in children. This example case demonstrates a variety of neuropsychiatric symptoms and treatment occurring during the first 18 months after diagnosis.
S117 Method: A healthy 15-year-old boy presented with a twoweek history of acute tremor in his hands and abnormal movement of his tongue. WD was confirmed biochemically, on imaging, liver biopsy and genetics. Copper chelation improved neurological symptoms. A few months later he appeared depressed (tearful and low energy with low selfesteem) and had symptoms of obsessive compulsive disorder (obsessional doubt). Citalopram was started. His symptoms quickly resolved but he became irritable, impulsive, disinhibited and was unable to sleep. Type 2 bipolar affective disorder was diagnosed. However, concurrent with the onset and persistence of these neuropsychiatric symptoms, liver function, neurology and serum copper levels were improving. This suggested at least partial response to therapy. Citalopram was withdrawn and Lithium carbonate and Olanzapine were added to treat his bipolar disorder. After 14 months, his psychiatric symptoms resolved and his school performance improved significantly. Conclusion: In our population of paediatric WD patients, we identified common neuropsychiatric symptoms including suicidality, affective disorder, psychosis, anxiety disorders, personality difficulties and cognitive deficits. The onset of these important symptoms can occur some time after starting treatment and may not be directly related to copper levels. Liaison between neurologists, psychiatrists and hepatologists is required to manage the different aspects of WD care. Clinical observations have led us to establish a WD multidisciplinary clinic. P310 Isolated brain stem lesions in complex I deficiency: report of two cases A. Aeby1 *, C. Vilain2 , D. Baleriaux3 , R. Van Coster4 , M. Abramowicz2 , P. Van Bogaert1 . 1 Departments of Pediatric Neurology, Hopital Erasme-ULB, Brussels, Belgium; 2 Department ˆ of Genetics, Hopital Erasme-ULB, Brussels, Belgium; 3 Department ˆ of Neuroradiology, Hopital Erasme-ULB, Brussels, Belgium; ˆ 4 Laboratorium voor Mitochondriaal Onderzoek, UZ Gent, Gent, Belgium Objective: Involvement of the basal ganglia, principally the putamen, has long been considered the hallmark of Leigh syndrome. Recent reports suggest that MRI lesions may be limited to brainstem. This presentation aims to illustrate this concept in siblings with complex I deficiency. Case report: The proband, a boy, was born after uneventfull pregnancy from first-degree consanguineous parents. At 4 months, he presented rotatory nystagmus, failure to thrive, irritability and axial hypotonia. Lactate in blood and CSF, organic acids and aminoacids in urine were normal. Brain MRI showed symmetric T2 hypersignal and T1 hyposignal extending through the mesencephalon (substantia nigra), the pons, the posterior part of the medulla, and the cervical spinal cord. Respiratory chain spectrophotometry in the muscle was normal. The child died at 6 months from respiratory insufficiency. His sister had a very similar clinical course, with rotatory nystagmus, failure to thrive, irritability and axial hypotonia from the age of 4 months. In blood, lactate was 5.2 mmol/l (N < 2) and lactate/pyruvate ratio was 22.3 (N < 10). In the CSF, lactate was 2.3 mmol/l (N < 2). Organic acids and aminoacids in urines were normal. Brain MRI revealed discrete symmetric T2 hypersignal and T1 hyposignal in the medulla. Respiratory chain spectrophotometry and blue native page analysis revealed a diminished complex I activity in the muscle. Homozygosity mapping indicated three genomic regions with common homozygous haplotypes, containing only a few mitochondrial genes. Search of causal mutation is in progress. Conclusion: Our presentation illustrates that Leigh syndrome in complex I deficiency may be revealed by symmetric lesions in the brain stem. One should carefully look at this region
P308 Observation of NO pathway in homocystinuria and phenylketonuria (PKU) N.K. Kanzelmeyer1 , D. Tsikas2 , H. Hartmann1 , S. Illsinger1 , 1 *. 1 Department of Paediatrics, Hannover A.M. Das1 , T. Lucke ¨ Medical School, Hannover, Germany; 2 Clinical Pharmacology, Hannover Medical School, Hannover, Germany Background: ADMA, an endogenous inhibitor of NO-synthase, has recently been identified as a cardiovascular risk factor. We studied the L-arginine NO-pathway in children with homocystinuria − a disease with well known cardiovascular risk − and with phenylketonurie (PKU). PKU, a disease with suspicious but not proven cardiovascular risk, was studied because tetrahydrobiopterin (BH4) is involved in both, phenylalanine degradation and NO-synthesis. Methods: ADMA in plasma and urine was determined by gas chromatography-tandem mass spectrometry (GC-MSMS). Nitrate and nitrite in plasma and urine were measured simultaneously by GC-MS. Results: Plasma ADMA levels in patients with homocystinuria were significantly higher than in healthy age-matched controls (660±158 versus 475±77 nmol/L, p = 0.035, n = 6). In patients with PKU ADMA plasma levels were significantly lower compared to age matched healthy controls (512±136 versus 585±125 nmol/L, p = 0.009; n = 52). Neither in the PKU group nor in two additional patients studied during the BH4 test, a clear correlation between ADMA and phenylalanine levels in plasma were found. Conclusion: Metabolism/elimination of ADMA is altered in children suffering from homocystinuria or PKU. However, delineation of the role of ADMA in these diseases demands further investigations. P309 Neuropsychiatry in paediatric Wilson’s disease − need for surveillance and management S. Mehta1,2,3 *, P. Hindley1,2,3 , A. Dhawan1 , M. Samuel1 , T. Hedderly1,2 . 1 Paediatric Neurosciences, King’s College Hospital and KHP, UK; 2 Paediatric Neurosciences, Evelina Children’s Hospital, GSTT, UK; 3 Institute of Psychiatry, South London and Maudsley, UK Objective: Wilson’s disease (WD) is an inherited disorder of copper metabolism known to present with hepatological, haematological and neuropsychiatric symptoms. There is little known about psychiatric symptoms in children. This example case demonstrates a variety of neuropsychiatric symptoms and treatment occurring during the first 18 months after diagnosis.
S117 Method: A healthy 15-year-old boy presented with a twoweek history of acute tremor in his hands and abnormal movement of his tongue. WD was confirmed biochemically, on imaging, liver biopsy and genetics. Copper chelation improved neurological symptoms. A few months later he appeared depressed (tearful and low energy with low selfesteem) and had symptoms of obsessive compulsive disorder (obsessional doubt). Citalopram was started. His symptoms quickly resolved but he became irritable, impulsive, disinhibited and was unable to sleep. Type 2 bipolar affective disorder was diagnosed. However, concurrent with the onset and persistence of these neuropsychiatric symptoms, liver function, neurology and serum copper levels were improving. This suggested at least partial response to therapy. Citalopram was withdrawn and Lithium carbonate and Olanzapine were added to treat his bipolar disorder. After 14 months, his psychiatric symptoms resolved and his school performance improved significantly. Conclusion: In our population of paediatric WD patients, we identified common neuropsychiatric symptoms including suicidality, affective disorder, psychosis, anxiety disorders, personality difficulties and cognitive deficits. The onset of these important symptoms can occur some time after starting treatment and may not be directly related to copper levels. Liaison between neurologists, psychiatrists and hepatologists is required to manage the different aspects of WD care. Clinical observations have led us to establish a WD multidisciplinary clinic. P310 Isolated brain stem lesions in complex I deficiency: report of two cases A. Aeby1 *, C. Vilain2 , D. Baleriaux3 , R. Van Coster4 , M. Abramowicz2 , P. Van Bogaert1 . 1 Departments of Pediatric Neurology, Hopital Erasme-ULB, Brussels, Belgium; 2 Department ˆ of Genetics, Hopital Erasme-ULB, Brussels, Belgium; 3 Department ˆ of Neuroradiology, Hopital Erasme-ULB, Brussels, Belgium; ˆ 4 Laboratorium voor Mitochondriaal Onderzoek, UZ Gent, Gent, Belgium Objective: Involvement of the basal ganglia, principally the putamen, has long been considered the hallmark of Leigh syndrome. Recent reports suggest that MRI lesions may be limited to brainstem. This presentation aims to illustrate this concept in siblings with complex I deficiency. Case report: The proband, a boy, was born after uneventfull pregnancy from first-degree consanguineous parents. At 4 months, he presented rotatory nystagmus, failure to thrive, irritability and axial hypotonia. Lactate in blood and CSF, organic acids and aminoacids in urine were normal. Brain MRI showed symmetric T2 hypersignal and T1 hyposignal extending through the mesencephalon (substantia nigra), the pons, the posterior part of the medulla, and the cervical spinal cord. Respiratory chain spectrophotometry in the muscle was normal. The child died at 6 months from respiratory insufficiency. His sister had a very similar clinical course, with rotatory nystagmus, failure to thrive, irritability and axial hypotonia from the age of 4 months. In blood, lactate was 5.2 mmol/l (N < 2) and lactate/pyruvate ratio was 22.3 (N < 10). In the CSF, lactate was 2.3 mmol/l (N < 2). Organic acids and aminoacids in urines were normal. Brain MRI revealed discrete symmetric T2 hypersignal and T1 hyposignal in the medulla. Respiratory chain spectrophotometry and blue native page analysis revealed a diminished complex I activity in the muscle. Homozygosity mapping indicated three genomic regions with common homozygous haplotypes, containing only a few mitochondrial genes. Search of causal mutation is in progress. Conclusion: Our presentation illustrates that Leigh syndrome in complex I deficiency may be revealed by symmetric lesions in the brain stem. One should carefully look at this region