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P275 A case of infantile Degos disease with neurological features
S106 P272 Natalizumab treatment in pediatric multiple sclerosis: three case reports G. Drake af Hagelsrum1 *, J. Lycke2 . 1The Queen Silvia Childrens Hospital, Goteborg University, Sahlgrenska University Hospital, ¨ Gothenburg, Sweden; 2 Department of Neurology, Goteborg ¨ University, Sahlgrenska University Hospital, Gothenburg, Sweden Background: The onset of multiple sclerosis (MS) in childhood before the age of 18 years occurs in an estimated range of 3−10% of all patients with MS. The initial course of the disease in pediatric MS is almost exclusively relapsingremittent. Although, the development of disability is usually slow, they will attain secondary progression and severe disability approximately 10 years before those with adult MS onset. Treatment of childhood MS with immunomodulatory therapies is based on strategies optimised for adult MS. Based on essentially open trials, the efficacy and safety of interferon beta in childhood MS has been equivalent with that reported for adults. Recent clinical studies have shown that natalizumab, a humanized antibody raised against alfa4 integrins, reduce the relative relapse rate in adults with 68% vs placebo and reduces gadolinium-enhancing lesions on MRI with >90%. Until now there are only a limited number of case reports on treatment with natalizumab in pediatric multiple sclerosis. We report three pediatric patients with MS that had high relapse rate from the onset. Brain-MRI showed persisting inflammatory activity and increase of lesions. All three patients received natalizumab as a first-line therapy due to high disease activity. Natalizumab 300 mg iv was given every 4 weeks. MRI and lumbar puncture was performed at start and after 12 months during treatment. During 24, 13 and 7 months of treatment no adverse events were seen. One patient showed significant improvements in her EDSS scores with no further relapses and follow-up MRI showed disapperance of gadolinium enhancing lesions. Natalizumab treatment was effective and seemed well tolerated in our patients. P273 Neurological features in Fusobacterial infection L. Carr1 , N. Desai1 , B. Peer Mohamed1 *. 1 Great Ormond Street Hospital for Children, London, UK Objective: To describe the neurological features in Fusobacterial infections. Method: Analysis of the clinical features in two children with Fusobacterial infection admitted to a paediatric neurology centre. Case 1: A fourteen-year-old boy was admitted with tonsillitis, neck stiffness, fever and paralysis of right sixth and twelfth cranial nerves. MRI scan demonstrated extensive leptomeningitis with left sigmoid sinus and internal jugular vein thrombosis. There was extra-dural abscess in the upper cervical spine and the clivus which enlarged after a few days, without causing medullary compression. It was treated conservatively. Fusobacterium necrophorum was isolated on blood culture. Appropriate antimicrobial therapy was continued leading to resolution of systemic symptoms and moderate improvement in cranial nerve palsies at 3 month review. Case 2: A fifteen-year-old girl was admitted with fever and headache. CT scan demonstrated frontal sinusitis. This failed to respond to intravenous antibiotics so was successfully drained by functional endoscopic sinus surgery. In the post-operative period, she developed generalised seizures and subsequent MRI scan revealed left frontal cerebritis with bilateral frontal subdural and parafalcine collections. Fusobacterium nucleatum was isolated on blood culture. Following surgical drainage of the subdural abscess
Posters and appropriate antimicrobial therapy, she made a good recovery. Discussion: Fusobacteria are anaerobic gram negative bacilli best known for causing Lemierre’s syndrome in which, oro-pharyngeal infection leads to internal jugular vein thrombosis and metastatic infections. The commonest species causing infection are F. necrophorum and F. nucleatum. In case 1, the clinical features were consistent with Lemierre’s syndrome in addition to manifestation of a clival pattern of neuropathy. In case 2, metastatic infection of brain parenchyma and subdural abscess led to seizures. Since Fusobacterial infections have a high mortality rate, prompt recognition is vital. These cases illustrate the variable neurological features secondary to this infection. P274 Alpers disease: does gender matter? K.A. Mohamed1 *, W. FathAlla1 , H. Parsons1 , E. Ahmed1 . Paediatric Neurology, SKMC, Abu Dhabi, UAE
1
Background: Alpers disease is a progressive cerebral and hepatic degeneration caused by a mutation in the gene encoding the catalytic subunit of mitochondrial DNA polymerase gamma (Pol gamma) involved in mitochondrial DNA (mtDNA) replication, the disease is progressive and fatal. Objective: To report on 5 successive cases from 3 families. Methods: Case review and literature search. Results: 5 patients from 3 extended families; all have clinical and radiological manifestations of the disease; this was confirmed by mutation analysis in four patients while one patient died before testing was possible. We observed that while the three females presented with advanced hepatic disease at the onset of neurological symptoms, the two males had normal hepatic function well after presentation with devastating neurological symptoms. It is acknowledged that the two tested males are distant relatives; however one of the three females was the sister of one male patient. Discussion: We are not aware of a gender influence of the phenotype in this disorder; most reports confirm the presence of both hepatic and brain disease at the time of confirmation, it is very unusual that both males in our series had no signs of liver disease for years after diagnosis. Conclusion: We hypothesize that initial manifestations in Alpers disease can be gender specific. In males, presentation with encephalopathy or focal status should raise the possibility of Alpers disease even in the absence of hepatic disease. P275 A case of infantile Degos disease with neurological features T.H. Yeo1 *, G. Vassallo1 , M. Judge1 , L.A. Jamieson2 , N. Laycock3 , A. Kelsey1 , P. Alwright4 , P. Riley1 , P. Brogan5 , B. Brown1 . 1 Royal Manchester Children’s Hospital, Manchester, United Kingdom; 2 Hope Hospital, Manchester, United Kingdom; 3 Blackpool Victoria Hospital, Blackpool, United Kingdom; 4 Booth Hall Children’s Hospital, Manchester, United Kingdom; 5 Great Ormond Street Hospital for Children, London, United Kingdom Background: Degos disease, also known as Malignant Atrophic Papulosis, is a rare vasculopathy of unknown etiology. The condition has characteristic skin lesions and other systemic features. We present a case of Degos disease with distinctive skin lesions, neurological involvement, sterile peritonitis and faltering growth. Case history: This female infant, the first child of nonconsanguineous parents, had no significant antenatal, birth and family history. She had two skin lesions at birth, and more erupted subsequently. These were slowly healing varioliform papules which were non-pruritic or tender, but sequentially scaled and scarred. The initial clinical diagnosis was Pityriasis-Lichenodes-et-Varioliformis-Acuta (PLEVA). At
Posters 8-week, she was investigated for chronic diarrhoea and faltering growth, but no cause was identified. At 9-month, she developed bilateral asymmetrical ptosis, and CT brain revealed calcification over left frontal, right parietotemporal and peri-3rd ventricular region. An underlying neurological diagnosis was suspected. Extensive investigations included negative Anti-AchR antibodies and negative response to pyridostigmine trial; normal CSF, TFTs, CRP/ESR, CK, ammonia, lactate, vasculitic/virology screen. LDH was 1033 u/l. Immunoglobulins, lymphocyte subsets and clonality studies were normal. Abdomen ultrasound showed mild hepatosplenomegaly. MRI brain was normal. Skin biopsy showed histological findings supportive of PLEVA but not diagnostic. At 14-month, she presented with recurrent sterile peritonitis. CT chest and abdomen showed bilateral pleural effusions, ascites and thickened bowel loops. Her skin lesions became polymorphic: purpuric macules, warty ulcerated nodules and white indented small scars. These lesions were distinctive of Degos disease. Conclusion: Our case highlights the severe and progressive course of Degos disease. The features of this condition need to be recognised by neurologists, as they can mimic several childhood neurological disorders. Degos disease with systemic involvement has a poor prognosis, there is no treatment and generally fatal as in this case. P276 Folinic acid substitution in Alpers disease O.E. Hasselmann1 *, N. Blau2 , V.T. Ramaekers3 , E.V. Quadros4 . 1 Pediatric Neurology, Ostschweizer Kinderspital, Switzerland; 2 University Hospital, Zurich, Switzerland; 3 Pediatric Neurology, ¨ University Hospital Li`ege Belgium; 4 Departments of Medicine and Cell Biology, SUNY Downstate Medical Centre, Brooklyn, NY, USA Objective: Alpers disease is a progressive neurodegenerative encephalopathy with multifocal seizures, developmental regression, cortical blindness and early death often due to hepatic failure. Mutations of the mitochondrial DNA polymerase gamma lead to an mitochondrial DNA depletion syndrome with reduced activity of respiratory chain complexes. Methods: Measurements of cytokines, neurotransmitter and 5-methyltetrahydrofolate were used as biological markers for a specific substitution therapy. Results: In a three year old girl with Alpers disease we saw increased neopterin, interleukins and interferon-gamma, reduced CSF 5-methyltetrahydrofolate and increased serum intrathecal folate receptor autoantibodies. Under substitution with pharmacological doses of folinic acid cerebral 5-methyltetrahydrofolate levels normalized, inflammatory parameters decreased leading to a clear clinical improvement over a time span of two and a half years. Interpretation: This case report provides new insights into aspects of the pathophysiology of Alpers disease, where mitochondrial dysfunction in conjunction with blocking folate receptor auto-antibodies can lead to a secondary cerebral folate deficiency syndrome. The treatment of the latter provides relief to the patient but fails to stop the underlying disease. Reference(s) Ramaekers VT, Rothenberg SP, Sequeira J et al. Autoantibodies against folate receptors of the choroid plexus block folate uptake and cause cerebral folate deficiency in childhood. NEJM. 2005; 352: 1985 1991.
S107 P277 Molecular basis of chaperone effect in lysosomal diseases Y. Suzuki1 *, K. Higaki2 , E. Nanba2 , K. Ohno3 , Y. Sakakibara4 , S. Ogawa4 , M. Iida5 . 1 Child Neurology and Rehabilitation, International University of Health and Welfare, Otawara, Japan; 2 Functional Genomics, Tottori Univeristy, Yonago, Japan; 3 Child Neurology, Tottori University, Yonago, Japan; 4 Biosciences and Informatics, Keio University, Yokohama, Japan; 5 Central Laboratories, Seikagaku Corporation, Higashi-Yamato, Japan Objective: To clarify the molecular basis of chaperone effect in the new molecular therapy for lysosomal diseases. Methods: In vitro analysis of mutant enzymes in somatic cells from patients with lysosomal diseases; correlative analysis of chaperone effect and enzyme inhibition; dose relationship between the oral chemical chaperone and tissue concentration; intracellular chaperone turnover in tissues, particularly in the brain; computational analysis for prediction of molecular interaction between the enzyme and chaperone under varying pH conditions; and analysis of chaperone dosage and clinical effect in experimental animals. Results: Mutant alpha-galactosidase, beta-galactosidase and beta-glucosidase molecules were unstable at high temperature and neutral pH conditions. This abnormality was corrected by nojirimycin, valienamine, bicyclic azasugar, and 1-N-iminosugar derivatives in addition to galactose. The chaperone effect was mutation- and structure-specific; they exhibited varying chaperone effects toward mutant enzymes, and structurally analogous chaperones showed heterogeneous chaperone spectrum. Binding free energy computation revealed that the chaperone enzyme complex is less stable with higher free energy at pH 5 than at pH 7, thus allowing spontaneous dissociation in the lysosome. Low dose chaperone treatment is effective for disease progression clinically. Conclusions: Each chaperone has its own molecular specificity toward the enzyme counterpart. Restoration of the enzyme depends on the steric conformation of the chaperone structure that determines stability of the chaperone enzyme complex. This hypothesis was theoretically confirmed by computation of the free energy under the acidic condition. The mutant enzyme is released and stable catalytic activity is expressed in the lysosome. The physicochemical chaperone property is critical to achieve expression of the mutant enzyme activity in the brain, particularly for intestinal absorption and passage through the blood brain barrier. We expect a higher chaperone effect by molecular analysis of this type for the establishment of chaperone therapy in the near future. P278 Characteristics of children with rare neurodegenerative diseases admitted in 2008 at department of child neurology, Ljubljana V. Kerin1 *, A. Fakin1 *, J. Kodric2 , D. Neubauer1,2 . 1 University of Ljubljana, Medical Faculty of Ljubljana, Slovenia; 2 University Medical Centre Ljubljana, Children’s Hospital, Deparment of Child, Adolescent and Developmental Neurology, Slovenia Background: We present the characteristics of 50 children with rare neurodegenerative diseases who were admitted to the Department of Child, Adolescent and Developmental Neurology, Children’s Hospital, University Medical Centre Ljubljana, in the year 2008. The work is done partly within the nEUroped project. Materials and Methods: Head circumference, body weight and diagnoses were gathered from the medical files. Children were assigned in five groups according to severity of their developmental and/or neurological deficit. Results: Twenty four boys and twenty six girls were admitted at the age range between 2 months and 19 years, the
Posters and appropriate antimicrobial therapy, she made a good recovery. Discussion: Fusobacteria are anaerobic gram negative bacilli best known for causing Lemierre’s syndrome in which, oro-pharyngeal infection leads to internal jugular vein thrombosis and metastatic infections. The commonest species causing infection are F. necrophorum and F. nucleatum. In case 1, the clinical features were consistent with Lemierre’s syndrome in addition to manifestation of a clival pattern of neuropathy. In case 2, metastatic infection of brain parenchyma and subdural abscess led to seizures. Since Fusobacterial infections have a high mortality rate, prompt recognition is vital. These cases illustrate the variable neurological features secondary to this infection. P274 Alpers disease: does gender matter? K.A. Mohamed1 *, W. FathAlla1 , H. Parsons1 , E. Ahmed1 . Paediatric Neurology, SKMC, Abu Dhabi, UAE
1
Background: Alpers disease is a progressive cerebral and hepatic degeneration caused by a mutation in the gene encoding the catalytic subunit of mitochondrial DNA polymerase gamma (Pol gamma) involved in mitochondrial DNA (mtDNA) replication, the disease is progressive and fatal. Objective: To report on 5 successive cases from 3 families. Methods: Case review and literature search. Results: 5 patients from 3 extended families; all have clinical and radiological manifestations of the disease; this was confirmed by mutation analysis in four patients while one patient died before testing was possible. We observed that while the three females presented with advanced hepatic disease at the onset of neurological symptoms, the two males had normal hepatic function well after presentation with devastating neurological symptoms. It is acknowledged that the two tested males are distant relatives; however one of the three females was the sister of one male patient. Discussion: We are not aware of a gender influence of the phenotype in this disorder; most reports confirm the presence of both hepatic and brain disease at the time of confirmation, it is very unusual that both males in our series had no signs of liver disease for years after diagnosis. Conclusion: We hypothesize that initial manifestations in Alpers disease can be gender specific. In males, presentation with encephalopathy or focal status should raise the possibility of Alpers disease even in the absence of hepatic disease. P275 A case of infantile Degos disease with neurological features T.H. Yeo1 *, G. Vassallo1 , M. Judge1 , L.A. Jamieson2 , N. Laycock3 , A. Kelsey1 , P. Alwright4 , P. Riley1 , P. Brogan5 , B. Brown1 . 1 Royal Manchester Children’s Hospital, Manchester, United Kingdom; 2 Hope Hospital, Manchester, United Kingdom; 3 Blackpool Victoria Hospital, Blackpool, United Kingdom; 4 Booth Hall Children’s Hospital, Manchester, United Kingdom; 5 Great Ormond Street Hospital for Children, London, United Kingdom Background: Degos disease, also known as Malignant Atrophic Papulosis, is a rare vasculopathy of unknown etiology. The condition has characteristic skin lesions and other systemic features. We present a case of Degos disease with distinctive skin lesions, neurological involvement, sterile peritonitis and faltering growth. Case history: This female infant, the first child of nonconsanguineous parents, had no significant antenatal, birth and family history. She had two skin lesions at birth, and more erupted subsequently. These were slowly healing varioliform papules which were non-pruritic or tender, but sequentially scaled and scarred. The initial clinical diagnosis was Pityriasis-Lichenodes-et-Varioliformis-Acuta (PLEVA). At
Posters 8-week, she was investigated for chronic diarrhoea and faltering growth, but no cause was identified. At 9-month, she developed bilateral asymmetrical ptosis, and CT brain revealed calcification over left frontal, right parietotemporal and peri-3rd ventricular region. An underlying neurological diagnosis was suspected. Extensive investigations included negative Anti-AchR antibodies and negative response to pyridostigmine trial; normal CSF, TFTs, CRP/ESR, CK, ammonia, lactate, vasculitic/virology screen. LDH was 1033 u/l. Immunoglobulins, lymphocyte subsets and clonality studies were normal. Abdomen ultrasound showed mild hepatosplenomegaly. MRI brain was normal. Skin biopsy showed histological findings supportive of PLEVA but not diagnostic. At 14-month, she presented with recurrent sterile peritonitis. CT chest and abdomen showed bilateral pleural effusions, ascites and thickened bowel loops. Her skin lesions became polymorphic: purpuric macules, warty ulcerated nodules and white indented small scars. These lesions were distinctive of Degos disease. Conclusion: Our case highlights the severe and progressive course of Degos disease. The features of this condition need to be recognised by neurologists, as they can mimic several childhood neurological disorders. Degos disease with systemic involvement has a poor prognosis, there is no treatment and generally fatal as in this case. P276 Folinic acid substitution in Alpers disease O.E. Hasselmann1 *, N. Blau2 , V.T. Ramaekers3 , E.V. Quadros4 . 1 Pediatric Neurology, Ostschweizer Kinderspital, Switzerland; 2 University Hospital, Zurich, Switzerland; 3 Pediatric Neurology, ¨ University Hospital Li`ege Belgium; 4 Departments of Medicine and Cell Biology, SUNY Downstate Medical Centre, Brooklyn, NY, USA Objective: Alpers disease is a progressive neurodegenerative encephalopathy with multifocal seizures, developmental regression, cortical blindness and early death often due to hepatic failure. Mutations of the mitochondrial DNA polymerase gamma lead to an mitochondrial DNA depletion syndrome with reduced activity of respiratory chain complexes. Methods: Measurements of cytokines, neurotransmitter and 5-methyltetrahydrofolate were used as biological markers for a specific substitution therapy. Results: In a three year old girl with Alpers disease we saw increased neopterin, interleukins and interferon-gamma, reduced CSF 5-methyltetrahydrofolate and increased serum intrathecal folate receptor autoantibodies. Under substitution with pharmacological doses of folinic acid cerebral 5-methyltetrahydrofolate levels normalized, inflammatory parameters decreased leading to a clear clinical improvement over a time span of two and a half years. Interpretation: This case report provides new insights into aspects of the pathophysiology of Alpers disease, where mitochondrial dysfunction in conjunction with blocking folate receptor auto-antibodies can lead to a secondary cerebral folate deficiency syndrome. The treatment of the latter provides relief to the patient but fails to stop the underlying disease. Reference(s) Ramaekers VT, Rothenberg SP, Sequeira J et al. Autoantibodies against folate receptors of the choroid plexus block folate uptake and cause cerebral folate deficiency in childhood. NEJM. 2005; 352: 1985 1991.
S107 P277 Molecular basis of chaperone effect in lysosomal diseases Y. Suzuki1 *, K. Higaki2 , E. Nanba2 , K. Ohno3 , Y. Sakakibara4 , S. Ogawa4 , M. Iida5 . 1 Child Neurology and Rehabilitation, International University of Health and Welfare, Otawara, Japan; 2 Functional Genomics, Tottori Univeristy, Yonago, Japan; 3 Child Neurology, Tottori University, Yonago, Japan; 4 Biosciences and Informatics, Keio University, Yokohama, Japan; 5 Central Laboratories, Seikagaku Corporation, Higashi-Yamato, Japan Objective: To clarify the molecular basis of chaperone effect in the new molecular therapy for lysosomal diseases. Methods: In vitro analysis of mutant enzymes in somatic cells from patients with lysosomal diseases; correlative analysis of chaperone effect and enzyme inhibition; dose relationship between the oral chemical chaperone and tissue concentration; intracellular chaperone turnover in tissues, particularly in the brain; computational analysis for prediction of molecular interaction between the enzyme and chaperone under varying pH conditions; and analysis of chaperone dosage and clinical effect in experimental animals. Results: Mutant alpha-galactosidase, beta-galactosidase and beta-glucosidase molecules were unstable at high temperature and neutral pH conditions. This abnormality was corrected by nojirimycin, valienamine, bicyclic azasugar, and 1-N-iminosugar derivatives in addition to galactose. The chaperone effect was mutation- and structure-specific; they exhibited varying chaperone effects toward mutant enzymes, and structurally analogous chaperones showed heterogeneous chaperone spectrum. Binding free energy computation revealed that the chaperone enzyme complex is less stable with higher free energy at pH 5 than at pH 7, thus allowing spontaneous dissociation in the lysosome. Low dose chaperone treatment is effective for disease progression clinically. Conclusions: Each chaperone has its own molecular specificity toward the enzyme counterpart. Restoration of the enzyme depends on the steric conformation of the chaperone structure that determines stability of the chaperone enzyme complex. This hypothesis was theoretically confirmed by computation of the free energy under the acidic condition. The mutant enzyme is released and stable catalytic activity is expressed in the lysosome. The physicochemical chaperone property is critical to achieve expression of the mutant enzyme activity in the brain, particularly for intestinal absorption and passage through the blood brain barrier. We expect a higher chaperone effect by molecular analysis of this type for the establishment of chaperone therapy in the near future. P278 Characteristics of children with rare neurodegenerative diseases admitted in 2008 at department of child neurology, Ljubljana V. Kerin1 *, A. Fakin1 *, J. Kodric2 , D. Neubauer1,2 . 1 University of Ljubljana, Medical Faculty of Ljubljana, Slovenia; 2 University Medical Centre Ljubljana, Children’s Hospital, Deparment of Child, Adolescent and Developmental Neurology, Slovenia Background: We present the characteristics of 50 children with rare neurodegenerative diseases who were admitted to the Department of Child, Adolescent and Developmental Neurology, Children’s Hospital, University Medical Centre Ljubljana, in the year 2008. The work is done partly within the nEUroped project. Materials and Methods: Head circumference, body weight and diagnoses were gathered from the medical files. Children were assigned in five groups according to severity of their developmental and/or neurological deficit. Results: Twenty four boys and twenty six girls were admitted at the age range between 2 months and 19 years, the