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OPL118 Peripheral neuropathy in a case of VWM disease carrying novel mutations of the EIF2B gene
$76
Oral Platform Abstracts
Wednesday, November 9, 2005
MRI endpoints included the number and volume of new or enlarging T2-hyperintense lesions, the number and volume of G d + lesions, and the number and volume of Tl-hypointense lesions. The effect of natalizumab on MRI endpoints was analyzed according to the following pre-specified subgroups based on patient characteristics at baseline: pre-study relapse number (1, 2, >3), EDSS score (i<3.5, >3.5), number of 1"2 lesions ( < 9 , _>9), presence of gadoliniumenhanced (Gd+) lesions (0, _>1), age (i<40, _>40 years), and gender (male, female). Results: Natalizumab's effects were consistent across subgroups. For example, over 1 year, those with G d + lesions at baseline developed 9.8 T2 lesions on placebo vs. 1.8 on natalizumab. Similarly, those without G d + lesions at baseline developed 3.0 1"2 lesions on placebo vs. 0.7 on natalizumab. Conclusion: The effect of natalizumab was consistent across these pre-specified subgroups at 1 year. Two-year data will also be presented.
Child Neurology OPLll5 Non-invaSive ventilalion in children with neurouluscular dJ.seN: a clinical and quality olLliii~ outCOme study
Young, H ~'3, Lowe, A t, Fitzgerald, D L~, Seton, C 1, Waters, K La, Kenny, E 1, North, K l'a.~, Ryan, M 1'~.~. 1The Children's Hospital at
Westmead, Sydney, Australia," 2The University of Sydney, Sydney, Australia; 3The Institute for Neuromuscular Research, Sydney, Australia Baekgxound: In recent years non-invasive ventilation (NIV) has been
used to treat respiratory failure in paediatric neuromuscular disease. There is relatively little data on long-term outcome in such cases. Clinical outcome and quality of life (QOL) with NIV was assessed in a cohort of clffldren with respiratory compromise associated with neuronmscular disease. Method: Records were reviewed and clinical data obtained from the year prior to commencing NIV and annually thereafter. Data obtained included: diagnosis, patient symptoms, mortality, NIV adverse effects, pulmonary function tests, polysomnographic data, length of hospitalisations and health service costs. Patients and parents completed questionnaires assessing QOL with NIV and recalling QOL before NIV. Results: 14 (of 17 -- 82%) patients enrolled. Follow up ranged from 6-84 months (median 30 months). After NIV symptoms of daytime sleepiness (p - 0.003) and headache (lJ - 0.046) improved significantly. Sleep quality assessed by polysomnography also improved significantly. Hospitalisation rates (p - 0.002) and health care costs (p 0.003) decreased significantly. QOL remained stable after NIV, despite disease progression, and there was a high degree of concordance in QOL as perceived by parents and patients. Conclusion: Treatment of respiratory failure with NIV, in paediatric neuromuscular disease, results in reduction in symptoms, hospitalisations and health care costs without adverse effects on QOL.
OPLI17 An Analysis of Oxyslerol Levels in tile Sera of Patients with NieInann-Pick C Disease and in tile Brains of N P C Mice
Tay, S 1, He, X 2, Jenner, A s, Ong, W 2, Wong, B2. 1Department of
Paediatries, National University Of Singapore; 2Department of Anatomy, National University of Singapore," SDepartment of Biochemistry, National University of Singapore Background: Niemann-Pick type C (NPC) disease is a rare neurode-
generative disorder characterized by defects of intracellular trafficking
of cholesterol. Cholesterol is synthesized endogenously in the brain and is converted to cholesterol oxidation products or oxysterols by direct oxidation or by oxysterol biosynthetic enzymes. Certain oxysterols such as 7-ketocholesterol and 24-hydroxycholesterol are toxic to neurons in culture. The present study aimed to elucidate the levels of cholesterol and cholesterol oxidation products in the serum o f NPC patients and the brains of the N P C mouse model. Methods: Seven-week old N P C mice were used as this is the age onset of symptoms in the N P C mice, correlating with the onset of irreversible damage to the cell bodies of neurons. Cholesterol and oxysterol levels were analyzed in different regions of the N P C mouse brain by GC/MS. Serum samples from 3 N P C patients were similarly analyzed. Agematched controls were used. Results: There was no significant difference in cholesterol or cholesterol oxidation products found between N P C mouse brains and controls, confirming no net accumulation of cholesterol in the brain. The serum of haman patients demonstrated increased 24-hydroxycholesterol levels compared with normal controls. Conclusion: The findings of increased 24-hydroxycholesterol in sera of N P C patients may suggest either increased turnover of cholesterol, or increased excretion of oxysterols from the brain. Tiffs is consistent with known reverse transport of oxysterols from the brain to the plasma in chronic neurodegenerative diseases such as Alzheimer's disease. Serum 24-hydroxycholesterol may be a useful biomarker for future clinical trials for children with NPC. OPLll8 Peripheral netucopattly in a case of V W M disease carxying novel iiluta[ions of tile EIF2B gene
Dotfi, M, Scali, O, Bianchi, S, De Stefano, N, Strornillo, ML, Malandrini, A, Federico, A. Dep. NeurologicalAnd Behavioural
Sciences, University Of Siena, Italy Background: Vanishing white matter (VWM) is an autosomal recessive
leukoencephalopathy with variable age of onset due to mutations in the genes encoding the five subunits of eukaryocytic initiation factor 2B (EIF2B). The clinical spectrum o f the disorder ranges from a severe rapidly progressive early infantile form to a slowly progressive or even asymptomatic adult phenotype. Typically, the disease results in episodic motor deterioration, particularly after head injury or infections. Peripheral nerve involvement has not been reported. Methods: The patient was a 4 year-old boy with progressive ataxia and spastidty since the age of 3 and normal intelligence. MRI showed diffuse bilateral leukoencephalopathy. Laboratory investigations included EMG, peripheral nerve conduction velocities and sural nerve biopsy. Following informed consent genomic D N A was isolated fi'om whole blood according to standard procedures. PCR was perforated with intronic primers specific for exons 2 and 6 of the EIF2B5 gene. PCR products were sequenced in both forward and reverse directions by automated sequencing. Results: Electrophysiological studies suggested the presence of a demyelinating peripheral neuropathy. Sural nerve biopsy evidenced demyelination and axonal damage. Sequence analysis of EIF2B5 gene exon 2 showed a previously unreported missense mutation TTG TCG in codon 203, resulting in the replacement of a leudne residue whit a serine. Sequence analysis of EIF2B5 gene exon 6 showed a novel missense mutation C G A C A A in codon 806, resulting in the replacement of an arginine residue whit a glutanffne. Conclusions: We describe here an early infantile case of VWM with electrophysiological and biopsy evidence of peripheral neuropathy, carrying two novel mutations of the EIF2B5 gene. To the best of our knowledge, peripheral nerve involvement has never been reported in patients with VWM. This case enlarges our knowledge of V W M disease phenotype and suggests that tiffs condition should be hypothesized even in cases with peripheral neuropathy. Further observations are needed to confirm a possible genotype/phenotype correlation.
Oral Platform Abstracts
Wednesday, November 9, 2005
MRI endpoints included the number and volume of new or enlarging T2-hyperintense lesions, the number and volume of G d + lesions, and the number and volume of Tl-hypointense lesions. The effect of natalizumab on MRI endpoints was analyzed according to the following pre-specified subgroups based on patient characteristics at baseline: pre-study relapse number (1, 2, >3), EDSS score (i<3.5, >3.5), number of 1"2 lesions ( < 9 , _>9), presence of gadoliniumenhanced (Gd+) lesions (0, _>1), age (i<40, _>40 years), and gender (male, female). Results: Natalizumab's effects were consistent across subgroups. For example, over 1 year, those with G d + lesions at baseline developed 9.8 T2 lesions on placebo vs. 1.8 on natalizumab. Similarly, those without G d + lesions at baseline developed 3.0 1"2 lesions on placebo vs. 0.7 on natalizumab. Conclusion: The effect of natalizumab was consistent across these pre-specified subgroups at 1 year. Two-year data will also be presented.
Child Neurology OPLll5 Non-invaSive ventilalion in children with neurouluscular dJ.seN: a clinical and quality olLliii~ outCOme study
Young, H ~'3, Lowe, A t, Fitzgerald, D L~, Seton, C 1, Waters, K La, Kenny, E 1, North, K l'a.~, Ryan, M 1'~.~. 1The Children's Hospital at
Westmead, Sydney, Australia," 2The University of Sydney, Sydney, Australia; 3The Institute for Neuromuscular Research, Sydney, Australia Baekgxound: In recent years non-invasive ventilation (NIV) has been
used to treat respiratory failure in paediatric neuromuscular disease. There is relatively little data on long-term outcome in such cases. Clinical outcome and quality of life (QOL) with NIV was assessed in a cohort of clffldren with respiratory compromise associated with neuronmscular disease. Method: Records were reviewed and clinical data obtained from the year prior to commencing NIV and annually thereafter. Data obtained included: diagnosis, patient symptoms, mortality, NIV adverse effects, pulmonary function tests, polysomnographic data, length of hospitalisations and health service costs. Patients and parents completed questionnaires assessing QOL with NIV and recalling QOL before NIV. Results: 14 (of 17 -- 82%) patients enrolled. Follow up ranged from 6-84 months (median 30 months). After NIV symptoms of daytime sleepiness (p - 0.003) and headache (lJ - 0.046) improved significantly. Sleep quality assessed by polysomnography also improved significantly. Hospitalisation rates (p - 0.002) and health care costs (p 0.003) decreased significantly. QOL remained stable after NIV, despite disease progression, and there was a high degree of concordance in QOL as perceived by parents and patients. Conclusion: Treatment of respiratory failure with NIV, in paediatric neuromuscular disease, results in reduction in symptoms, hospitalisations and health care costs without adverse effects on QOL.
OPLI17 An Analysis of Oxyslerol Levels in tile Sera of Patients with NieInann-Pick C Disease and in tile Brains of N P C Mice
Tay, S 1, He, X 2, Jenner, A s, Ong, W 2, Wong, B2. 1Department of
Paediatries, National University Of Singapore; 2Department of Anatomy, National University of Singapore," SDepartment of Biochemistry, National University of Singapore Background: Niemann-Pick type C (NPC) disease is a rare neurode-
generative disorder characterized by defects of intracellular trafficking
of cholesterol. Cholesterol is synthesized endogenously in the brain and is converted to cholesterol oxidation products or oxysterols by direct oxidation or by oxysterol biosynthetic enzymes. Certain oxysterols such as 7-ketocholesterol and 24-hydroxycholesterol are toxic to neurons in culture. The present study aimed to elucidate the levels of cholesterol and cholesterol oxidation products in the serum o f NPC patients and the brains of the N P C mouse model. Methods: Seven-week old N P C mice were used as this is the age onset of symptoms in the N P C mice, correlating with the onset of irreversible damage to the cell bodies of neurons. Cholesterol and oxysterol levels were analyzed in different regions of the N P C mouse brain by GC/MS. Serum samples from 3 N P C patients were similarly analyzed. Agematched controls were used. Results: There was no significant difference in cholesterol or cholesterol oxidation products found between N P C mouse brains and controls, confirming no net accumulation of cholesterol in the brain. The serum of haman patients demonstrated increased 24-hydroxycholesterol levels compared with normal controls. Conclusion: The findings of increased 24-hydroxycholesterol in sera of N P C patients may suggest either increased turnover of cholesterol, or increased excretion of oxysterols from the brain. Tiffs is consistent with known reverse transport of oxysterols from the brain to the plasma in chronic neurodegenerative diseases such as Alzheimer's disease. Serum 24-hydroxycholesterol may be a useful biomarker for future clinical trials for children with NPC. OPLll8 Peripheral netucopattly in a case of V W M disease carxying novel iiluta[ions of tile EIF2B gene
Dotfi, M, Scali, O, Bianchi, S, De Stefano, N, Strornillo, ML, Malandrini, A, Federico, A. Dep. NeurologicalAnd Behavioural
Sciences, University Of Siena, Italy Background: Vanishing white matter (VWM) is an autosomal recessive
leukoencephalopathy with variable age of onset due to mutations in the genes encoding the five subunits of eukaryocytic initiation factor 2B (EIF2B). The clinical spectrum o f the disorder ranges from a severe rapidly progressive early infantile form to a slowly progressive or even asymptomatic adult phenotype. Typically, the disease results in episodic motor deterioration, particularly after head injury or infections. Peripheral nerve involvement has not been reported. Methods: The patient was a 4 year-old boy with progressive ataxia and spastidty since the age of 3 and normal intelligence. MRI showed diffuse bilateral leukoencephalopathy. Laboratory investigations included EMG, peripheral nerve conduction velocities and sural nerve biopsy. Following informed consent genomic D N A was isolated fi'om whole blood according to standard procedures. PCR was perforated with intronic primers specific for exons 2 and 6 of the EIF2B5 gene. PCR products were sequenced in both forward and reverse directions by automated sequencing. Results: Electrophysiological studies suggested the presence of a demyelinating peripheral neuropathy. Sural nerve biopsy evidenced demyelination and axonal damage. Sequence analysis of EIF2B5 gene exon 2 showed a previously unreported missense mutation TTG TCG in codon 203, resulting in the replacement of a leudne residue whit a serine. Sequence analysis of EIF2B5 gene exon 6 showed a novel missense mutation C G A C A A in codon 806, resulting in the replacement of an arginine residue whit a glutanffne. Conclusions: We describe here an early infantile case of VWM with electrophysiological and biopsy evidence of peripheral neuropathy, carrying two novel mutations of the EIF2B5 gene. To the best of our knowledge, peripheral nerve involvement has never been reported in patients with VWM. This case enlarges our knowledge of V W M disease phenotype and suggests that tiffs condition should be hypothesized even in cases with peripheral neuropathy. Further observations are needed to confirm a possible genotype/phenotype correlation.