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G.P.93 Study of a novel autosomal dominant spinocerebellar ataxia
870
Abstracts / Neuromuscular Disorders 22 (2012) 804–908
lings are affected, and the parents are second cousins, suggesting a recessive disease. The two affected brothers presented at 55 and 54 years respectively with weakness about the ankles, poor balance and chronic cough. There were cerebellar signs with saccadic interruption of eye movements and a wide-based gait, and later on dysarthria. Creatine kinase was elevated, to between 580 and 1020 (N < 195). Nerve conduction studies showed a severe sensorimotor peripheral neuropathy and muscle biopsy showed numerous atrophic fibres and group atrophy, in keeping with a neurogenic cause. Electron microscopy additionally showed subsarcolemmal accumulation of pleomorphic mitochondria with large electron dense inclusions. MRI of the head showed progressive atrophy of the cerebellum, principally of the vermis, and thinning of the brainstem. No cause for the cough has been found. This combination of pathologies has not previously not been described in the literature, thus suggesting that this is a novel phenotype of recessive spinocerebellar ataxia. We have combined SNP-based linkage analysis with whole exome capture and next generation sequencing to attempt to identify the causative mutation in this family. Linkage exclusion analysis combined with whole exome sequencing has eliminated all known autosomal recessive spinocerebellar ataxia disease genes, indicating that a novel disease gene may be the cause of disease in this family. http://dx.doi:10.1016/j.nmd.2012.06.222
G.P.93 Study of a novel autosomal dominant spinocerebellar ataxia P.J. Lamont 1, K.S. Yau 2, R.M. Duff 2, W. Carroll 3, M.R. Davis 4, N.G. Laing 2 1 Royal Perth Hospital, Neurogenetics, Perth, Australia; 2 Western Australian Institute for Medical Research and the Centre for Medical Research, University of Western Australia, Perth, Australia; 3 Sir Charles Gairdner Hospital, Neurology, Perth, Australia; 4 Royal Perth Hospital, Anatomical Pathology, Perth, Australia The spinocerebellar ataxias are a clinically and genetically heterogeneous group of neurodegenerative disorders. There are currently 18 known disease genes and nine other loci that have been associated with autosomal dominant spinocerebellar ataxia. Because of this genetic heterogeneity, a large number of cases still go without a genetic diagnosis. The family under investigation is a four-generation family of Anglo-Saxon lineage, with eight known affected members. The phenotype is of an autosomal dominant spinocerebellar ataxia, with evidence of anticipation. The initial symptom is gait ataxia, followed within 5 years by slurring dysarthria, saccadic interruption of eye movements, intention tremor, and clumsy hand movements. There is evidence of long tract involvement with increased deep tendon reflexes in the legs and urinary urgency. There is progression of all the symptoms, with the second generation requiring a wheelchair by 70 years, and the third generation by 50 years. Progressive atrophy of the cerebellum, brain stem and cerebellar peduncles develops on MRI. All other investigations were within normal limits. Molecular testing for trinucleotide repeat expansions for SCA 1, 2, 3, 6, 7, 8 and 17 was negative. We then used SNP-based linkage analysis to attempt to identify the causative locus in the family. SNP linkage analysis excluded all known autosomal dominant spinocerebellar ataxia disease genes except for SCA8 (already excluded) and (SCA10). SCA10 has not as yet been excluded. However, mutations in this gene have only been reported in families of South American or Mexican descent, and the phenotype is usually complicated with seizures and mood disorders, unlike our family. The SCA 19/22, 21 and 29 loci were not excluded. Thus, the disease in our family is either caused by a novel disease gene, or it is the first SCA10 family outside of South America and Mexico to be described. http://dx.doi:10.1016/j.nmd.2012.06.223
G.P.94 Incidence and severity of peripheral neuropathy in children on vincristine – Do vitamin E levels change during treatment? M.P. Kava 1, P. Walsh 1, A. Berroya 1, Y. Halstead 1, R.M. Srinivasjois 2, B. Lewis 3, C. Cole 4, D. Baker 4, L. Nagarajan 1 1 Princess Margaret Hospital, Neurology, Perth, Australia; 2 Joondalup Health Campus, Paediatrics, Perth, Australia; 3 Princess Margaret Hospital, Biochemistry, Perth, Australia; 4 Princess Margaret Hospital, Oncology, Perth, Australia Chemotherapy induced peripheral neuropathy (PN) is a common dose limiting side effect associated with vincristine treatment. The painful sensori motor neuropathy seen in vincristine is similar to that in vitamin E deficiency. To determine the incidence, severity and type of PN associated with vincristine chemotherapy in children and to determine the levels of Vitamin E in the blood before and after starting vincristine. All children in the oncology unit of a tertiary paediatric hospital on vincristine were included. A detailed history,specifically tailored neurological examination and nerve conduction studies were performed and blood vitamin E levels were measured at baseline and at 3, 6 and 12 months from the time of chemotherapy. Thirty patients were enrolled over a period of 12 months. The mean age of the children was 6.2 years. 14/28(50%) children had pre B acute lymphoblastic leukemia. Peripheral neuropathy was evident in more than 90% patients. The most common subjective features of PN were weakness seen in 39% and pain in 30% at 3 months. The most common objective finding was loss of ankle reflex seen in 57% at 3 months and reduced ankle reflex in a further 21%. The subjective weakness disappeared and the pain reduced at 12 months while the objective signs persisted. The most common autonomic feature was constipation seen in 43% at 3 months. The most common nerve affected was the deep peroneal nerve with axonal involvement in 82% of the subjects tested. The vitamin E levels dropped significantly at 3, 6 and 12 months from baseline although they still remained within normal limits. More than 90% children on vincristine had evidence of neuropathy. It was mild sensorimotor axonal neuropathy that appeared within 3 months of treatment in most. The levels of vitamin E remained in the normal range though there was a significant drop at 3 months, followed by values lower than baseline at 6 and 12 months. http://dx.doi:10.1016/j.nmd.2012.06.224
G.P.95 Two sibs with early onset myopathy with areflexia, respiratory distress, and dysphagia (EMARDD) due to homozygous exon 7 deletion in MEGF10 K.G. Meilleur 1, T.M. Pierson 1, M. Jain 2, S. Donkervoort 1, T. Markello 3, L. Wolfe 3, J. Accardi 3, D. Adams 3, M. Sincan 3, K. Fuentes-Fajardo 3, P.F. Cherukuri 3, P. Cruz 4, I. Bajraktari 1, T. Lehky 1, J.K. Teer 3, J.C. Mullikin 4, W.A. Gahl 3, C.F. Boerkoel 3, C.J. Tifft 3, C.G. Bonnemann 1 1 National Institutes of Health, National Institute of Neurological Disorders and Stroke, Bethesda, United States; 2 National Institutes of Health, Rehabilitation, Bethesda, United States; 3 National Institutes of Health, National Human Genome Research Institute, Bethesda, United States; 4 National Institutes of Health, NIH Intramural Sequencing Center, Rockville, United States MEGF10 was recently implicated as the gene causing EMARDD. We present two consanguineous sibs with EMARDD, a 12-yr-old girl of Egyptian descent and her (deceased) older sister. The proband had decreased fetal movements and, at birth, diffuse hypotonia and finger contractures. At 8 months, she underwent a Nissen fundoplication with gastrostomy tube placement and after required ventilatory support resulting in a tracheostomy. She ambulated with a walker at 2 years of
Abstracts / Neuromuscular Disorders 22 (2012) 804–908
lings are affected, and the parents are second cousins, suggesting a recessive disease. The two affected brothers presented at 55 and 54 years respectively with weakness about the ankles, poor balance and chronic cough. There were cerebellar signs with saccadic interruption of eye movements and a wide-based gait, and later on dysarthria. Creatine kinase was elevated, to between 580 and 1020 (N < 195). Nerve conduction studies showed a severe sensorimotor peripheral neuropathy and muscle biopsy showed numerous atrophic fibres and group atrophy, in keeping with a neurogenic cause. Electron microscopy additionally showed subsarcolemmal accumulation of pleomorphic mitochondria with large electron dense inclusions. MRI of the head showed progressive atrophy of the cerebellum, principally of the vermis, and thinning of the brainstem. No cause for the cough has been found. This combination of pathologies has not previously not been described in the literature, thus suggesting that this is a novel phenotype of recessive spinocerebellar ataxia. We have combined SNP-based linkage analysis with whole exome capture and next generation sequencing to attempt to identify the causative mutation in this family. Linkage exclusion analysis combined with whole exome sequencing has eliminated all known autosomal recessive spinocerebellar ataxia disease genes, indicating that a novel disease gene may be the cause of disease in this family. http://dx.doi:10.1016/j.nmd.2012.06.222
G.P.93 Study of a novel autosomal dominant spinocerebellar ataxia P.J. Lamont 1, K.S. Yau 2, R.M. Duff 2, W. Carroll 3, M.R. Davis 4, N.G. Laing 2 1 Royal Perth Hospital, Neurogenetics, Perth, Australia; 2 Western Australian Institute for Medical Research and the Centre for Medical Research, University of Western Australia, Perth, Australia; 3 Sir Charles Gairdner Hospital, Neurology, Perth, Australia; 4 Royal Perth Hospital, Anatomical Pathology, Perth, Australia The spinocerebellar ataxias are a clinically and genetically heterogeneous group of neurodegenerative disorders. There are currently 18 known disease genes and nine other loci that have been associated with autosomal dominant spinocerebellar ataxia. Because of this genetic heterogeneity, a large number of cases still go without a genetic diagnosis. The family under investigation is a four-generation family of Anglo-Saxon lineage, with eight known affected members. The phenotype is of an autosomal dominant spinocerebellar ataxia, with evidence of anticipation. The initial symptom is gait ataxia, followed within 5 years by slurring dysarthria, saccadic interruption of eye movements, intention tremor, and clumsy hand movements. There is evidence of long tract involvement with increased deep tendon reflexes in the legs and urinary urgency. There is progression of all the symptoms, with the second generation requiring a wheelchair by 70 years, and the third generation by 50 years. Progressive atrophy of the cerebellum, brain stem and cerebellar peduncles develops on MRI. All other investigations were within normal limits. Molecular testing for trinucleotide repeat expansions for SCA 1, 2, 3, 6, 7, 8 and 17 was negative. We then used SNP-based linkage analysis to attempt to identify the causative locus in the family. SNP linkage analysis excluded all known autosomal dominant spinocerebellar ataxia disease genes except for SCA8 (already excluded) and (SCA10). SCA10 has not as yet been excluded. However, mutations in this gene have only been reported in families of South American or Mexican descent, and the phenotype is usually complicated with seizures and mood disorders, unlike our family. The SCA 19/22, 21 and 29 loci were not excluded. Thus, the disease in our family is either caused by a novel disease gene, or it is the first SCA10 family outside of South America and Mexico to be described. http://dx.doi:10.1016/j.nmd.2012.06.223
G.P.94 Incidence and severity of peripheral neuropathy in children on vincristine – Do vitamin E levels change during treatment? M.P. Kava 1, P. Walsh 1, A. Berroya 1, Y. Halstead 1, R.M. Srinivasjois 2, B. Lewis 3, C. Cole 4, D. Baker 4, L. Nagarajan 1 1 Princess Margaret Hospital, Neurology, Perth, Australia; 2 Joondalup Health Campus, Paediatrics, Perth, Australia; 3 Princess Margaret Hospital, Biochemistry, Perth, Australia; 4 Princess Margaret Hospital, Oncology, Perth, Australia Chemotherapy induced peripheral neuropathy (PN) is a common dose limiting side effect associated with vincristine treatment. The painful sensori motor neuropathy seen in vincristine is similar to that in vitamin E deficiency. To determine the incidence, severity and type of PN associated with vincristine chemotherapy in children and to determine the levels of Vitamin E in the blood before and after starting vincristine. All children in the oncology unit of a tertiary paediatric hospital on vincristine were included. A detailed history,specifically tailored neurological examination and nerve conduction studies were performed and blood vitamin E levels were measured at baseline and at 3, 6 and 12 months from the time of chemotherapy. Thirty patients were enrolled over a period of 12 months. The mean age of the children was 6.2 years. 14/28(50%) children had pre B acute lymphoblastic leukemia. Peripheral neuropathy was evident in more than 90% patients. The most common subjective features of PN were weakness seen in 39% and pain in 30% at 3 months. The most common objective finding was loss of ankle reflex seen in 57% at 3 months and reduced ankle reflex in a further 21%. The subjective weakness disappeared and the pain reduced at 12 months while the objective signs persisted. The most common autonomic feature was constipation seen in 43% at 3 months. The most common nerve affected was the deep peroneal nerve with axonal involvement in 82% of the subjects tested. The vitamin E levels dropped significantly at 3, 6 and 12 months from baseline although they still remained within normal limits. More than 90% children on vincristine had evidence of neuropathy. It was mild sensorimotor axonal neuropathy that appeared within 3 months of treatment in most. The levels of vitamin E remained in the normal range though there was a significant drop at 3 months, followed by values lower than baseline at 6 and 12 months. http://dx.doi:10.1016/j.nmd.2012.06.224
G.P.95 Two sibs with early onset myopathy with areflexia, respiratory distress, and dysphagia (EMARDD) due to homozygous exon 7 deletion in MEGF10 K.G. Meilleur 1, T.M. Pierson 1, M. Jain 2, S. Donkervoort 1, T. Markello 3, L. Wolfe 3, J. Accardi 3, D. Adams 3, M. Sincan 3, K. Fuentes-Fajardo 3, P.F. Cherukuri 3, P. Cruz 4, I. Bajraktari 1, T. Lehky 1, J.K. Teer 3, J.C. Mullikin 4, W.A. Gahl 3, C.F. Boerkoel 3, C.J. Tifft 3, C.G. Bonnemann 1 1 National Institutes of Health, National Institute of Neurological Disorders and Stroke, Bethesda, United States; 2 National Institutes of Health, Rehabilitation, Bethesda, United States; 3 National Institutes of Health, National Human Genome Research Institute, Bethesda, United States; 4 National Institutes of Health, NIH Intramural Sequencing Center, Rockville, United States MEGF10 was recently implicated as the gene causing EMARDD. We present two consanguineous sibs with EMARDD, a 12-yr-old girl of Egyptian descent and her (deceased) older sister. The proband had decreased fetal movements and, at birth, diffuse hypotonia and finger contractures. At 8 months, she underwent a Nissen fundoplication with gastrostomy tube placement and after required ventilatory support resulting in a tracheostomy. She ambulated with a walker at 2 years of