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0206 Haplotype studies in small ALS families: usefulness in the search for new genes causing ALS
S152
Poster Abstracts
Monday, November 7, 2005
out in 11 patients. Over 80 family members were examined in one family and bloods drawn for mutation analysis. Results: There was parental consanguinity in four of six affected sib ships, and probably in a fifth. Seven affected individuals were homozygous for a gross deletion including exons 70-73 of VPS13A and exons 6-7 of the adjacent gene GNA14 (EX70-EX73del). All these patients shared a c o m m o n haplotype in the same region. Two affected females in one family were homozygous for a splicing mutation 4 2 4 2 + 1 G > T, whereas their two male cousins were heterozygous for EX70-EX73del and 4242+1 G > T. Of nine patients with the deletion, including two who were heterozygous, seven had epilepsy (77%). Conclusion: The identification o f a c o m m o n 9q21 hap lotyp e associated with EX70-EX73del in four apparently unrelated French-Canadian ChAc families implies that C h A c shows a founder effect in FrenchCanadians, and that routine testing for EX70-EX73del in suspected ChAc cases m a y be worthwhile in tiffs population. Genotypephenotype correlation suggests that the deletion mutation is strongly associated with epilepsy. 0203 Mutational Analysis of the Neutolilamen! Light Chain (NEFL) Gene in Patients with Chareot-Marie-Tooth disease Choi, K, Clio, H, Choi, B. Department of Neurology, College of
Medicine, Ewha Womans University Background & Objectives: Charcot-Marie-Tooth (CMT) disease is the most c o m m o n form of inherited motor and sensory neuropathy. Neurofilament light chain polypeptide (NEFL) is one of the most a b u n d a n t cytoskeletal components of the neuron. NEFL gene encoding the neurofilament light chain plays an important role in mxonal structure that includes an extensive fibrous network in the cytoplasm of the neuron. Mutations in NEFL gene present in CMT2E, C M T type 1 and Dejerine-Sottas syndrome. However, there was no report to investigate the NEFL genes in K o r e a n C M T patients. Therefore, we investigated to find the clinical characteristics in patients with NEFL gene mutation. Methods: We examined mutations of NEFL gene in 125 Korean families diagnosed as having C M T disease. Mutations were confirmed by both strands sequendng. Nerve conduction studies were carried out C M T patients having each mutation. Results: As a result, 3 pathogenic mutations were found in 3 families, and 2 polymorphisms in 2 fanfflies. Two mutations (Leu334Pro, Pro22Arg) were determined to novel, and those were n o t detected in 105 healthy controls. A de novo missense mutation was found in a C M T family with NEFL mutation. The frequency of NEFL m u t a t i o n was 2.4%, which was similar in Europeans, a n d lower than those found in Japanese. Pro22Arg and Glu397Lys mutations show demyelinating neuropathy and Leu334pro mutation shows axonal neuropathy. Conclusion: We found NEFL mutations in patients with sporadic or dominantly inherited CMT. NEFL mutations should be considered in evaluation of C M T or related neuropathy with various clinical features. 0204 The iilOleOular basis of homoeysfinutia in Qatar M Fawzi Elsaid l, R a m i n Badii ~, M. S. Bessisso 1, N o o r a Shahbek 3, Mariam G EIAIi 3, Mariam Elmarikhie ~, M Elzyoid 3. Neurologj,
Genetics 2, Metabolic3, Hamad medical corporation, Doha, Qatar, Arabian Gulf" Introduction: Homocystinuria is the most c o m m o n inborn error of sulphur amino acid metabolism with global incidence of an estimated global incidence of 1:344,000 live births. To date 131 mutations have been detected in the CBS (cystathionine beta-synthase gene). Despite of that, no study h a s reported on the incidence of any mutations in patients from Gulf area. In order to know the molecular basis of the disease; genetic survey for all homocysteinuric patients were done.
Knowing the local mutation in Qatar; will help for future heath planning. Objective: To identify the incidence of gene mutations in local Arab population. Method: Prospective study of all patients w h o m clinically diagnosed as homocysteinuria through Fully sequencing of CBS and M T H F R C677T genes. Results: We report on an indigenous Arabian population in the State of Qatar with a n estimated 1 in 5,000 incidence ofhomocystinuria. The sequencing data identified the presence o f homozygous c o m m o n R336C (c.1006C>T) missense m u t a t i o n in exon 9 of the CBS gene. Also patients were found to be heterozygous for ( M T H F R ) gene mutation C677T. Further mutation analysis o f 55 affected members of the same tribe confirmed the R336C as the prevalent CBS mutation. Conclusion: We have the highest incidence of the disease all over the world. Tiffs mutation is knovat as B6-nonresponsive patients that is severe mutation without residual activity and is associated with severe clinical phenotypes. Identification of this mutation will provide essential information for carrier testing, premarital counseling, prenatal diagnosis and early diagnosis of the disease in this population.
0205 A Novel O P A l mutation in a Fanfily with AutusOiilal Donfinant Optic Atrophy Federieo, A, Cardaioli, E, Galhis, G N , Malfatti, E, D a Pozzo, P, Franceschini, R, Caporossi, A, Dotti, MT. Dep.Neurological And
Behavioural Sciences, University Of Siena, Italy Heading: To identify pathogenic mutations in patients with A D O A , previously excluded for L H O N mutations. Background: Autosomal dominant optic atrophy (ADOA), Kjer type, is an inherited primary optic neuropathy that leads to reduced visual acuity. It presents with an insidious onset of variable visual loss, optic nerve pallor, centrocaecal visual field scotoma and colour vision deficit, t-Iistopathological studies suggest that the underlying defect is due to retinal ganglion cells degeneration, as found in Leber Hereditary Optic. Neuropathy (LHHON). Genetic linkage studies localized a dominant optic atrophy gene (OPAl; OMIMI65500) to chromosome 3q28ter. OPAl encodes a large GTPase related to dynanffns, implicated in the fomtafion a n d the maintenance of the mitochondrial network. Titus, A D O A seems to be due to intpaitment of the mitochondrial function. To date more than 70 mutations in about 250 A D O A patients have been reported in literature. Most of them (90%) are distributed from exons 8 to 28 with the majority in the GTPase domain. In particular almost 50% of the mutations are localized in exons 8, 9, 12 and 27. Methods: Genomic D N A was extracted fi'om leukocytes of two siblings with optic, atrophy. Exons 8, 9, 12 and 27 were amplified by polymerase chain reaction and directly sequenced. Results: One novel nonsense mutation was detected in exon 9, R312Stop, resulting from a C > T transition at position c.934. This sequence variation h a s n o t been previously reported. Conclusions: The exon 9 truncative m u t a t i o n found in this fanffly stress the importance to screen exons 8, 9, 12 and 27. The discovery of new mutations in O P A l leads us to concentrate our efforts on A D O A pathogenesis. The link between O P A l and apoptosis give clues of the possible pathophysiological effect of the m u t a t i o n that leads to neurodegeneration of the retinal ganglion cells. A full comprehension of tiffs mechanism could help us understanding L H O N pathogenesis. In conclusion, can Leber's and Kjer's diseases be considered variation on the same theme?
0206 Haplotype studies in sman ALS fanfilies: usefulness in tile search for new genes causing A L S
Poster Abstracts
Monday, November 7, 2005
out in 11 patients. Over 80 family members were examined in one family and bloods drawn for mutation analysis. Results: There was parental consanguinity in four of six affected sib ships, and probably in a fifth. Seven affected individuals were homozygous for a gross deletion including exons 70-73 of VPS13A and exons 6-7 of the adjacent gene GNA14 (EX70-EX73del). All these patients shared a c o m m o n haplotype in the same region. Two affected females in one family were homozygous for a splicing mutation 4 2 4 2 + 1 G > T, whereas their two male cousins were heterozygous for EX70-EX73del and 4242+1 G > T. Of nine patients with the deletion, including two who were heterozygous, seven had epilepsy (77%). Conclusion: The identification o f a c o m m o n 9q21 hap lotyp e associated with EX70-EX73del in four apparently unrelated French-Canadian ChAc families implies that C h A c shows a founder effect in FrenchCanadians, and that routine testing for EX70-EX73del in suspected ChAc cases m a y be worthwhile in tiffs population. Genotypephenotype correlation suggests that the deletion mutation is strongly associated with epilepsy. 0203 Mutational Analysis of the Neutolilamen! Light Chain (NEFL) Gene in Patients with Chareot-Marie-Tooth disease Choi, K, Clio, H, Choi, B. Department of Neurology, College of
Medicine, Ewha Womans University Background & Objectives: Charcot-Marie-Tooth (CMT) disease is the most c o m m o n form of inherited motor and sensory neuropathy. Neurofilament light chain polypeptide (NEFL) is one of the most a b u n d a n t cytoskeletal components of the neuron. NEFL gene encoding the neurofilament light chain plays an important role in mxonal structure that includes an extensive fibrous network in the cytoplasm of the neuron. Mutations in NEFL gene present in CMT2E, C M T type 1 and Dejerine-Sottas syndrome. However, there was no report to investigate the NEFL genes in K o r e a n C M T patients. Therefore, we investigated to find the clinical characteristics in patients with NEFL gene mutation. Methods: We examined mutations of NEFL gene in 125 Korean families diagnosed as having C M T disease. Mutations were confirmed by both strands sequendng. Nerve conduction studies were carried out C M T patients having each mutation. Results: As a result, 3 pathogenic mutations were found in 3 families, and 2 polymorphisms in 2 fanfflies. Two mutations (Leu334Pro, Pro22Arg) were determined to novel, and those were n o t detected in 105 healthy controls. A de novo missense mutation was found in a C M T family with NEFL mutation. The frequency of NEFL m u t a t i o n was 2.4%, which was similar in Europeans, a n d lower than those found in Japanese. Pro22Arg and Glu397Lys mutations show demyelinating neuropathy and Leu334pro mutation shows axonal neuropathy. Conclusion: We found NEFL mutations in patients with sporadic or dominantly inherited CMT. NEFL mutations should be considered in evaluation of C M T or related neuropathy with various clinical features. 0204 The iilOleOular basis of homoeysfinutia in Qatar M Fawzi Elsaid l, R a m i n Badii ~, M. S. Bessisso 1, N o o r a Shahbek 3, Mariam G EIAIi 3, Mariam Elmarikhie ~, M Elzyoid 3. Neurologj,
Genetics 2, Metabolic3, Hamad medical corporation, Doha, Qatar, Arabian Gulf" Introduction: Homocystinuria is the most c o m m o n inborn error of sulphur amino acid metabolism with global incidence of an estimated global incidence of 1:344,000 live births. To date 131 mutations have been detected in the CBS (cystathionine beta-synthase gene). Despite of that, no study h a s reported on the incidence of any mutations in patients from Gulf area. In order to know the molecular basis of the disease; genetic survey for all homocysteinuric patients were done.
Knowing the local mutation in Qatar; will help for future heath planning. Objective: To identify the incidence of gene mutations in local Arab population. Method: Prospective study of all patients w h o m clinically diagnosed as homocysteinuria through Fully sequencing of CBS and M T H F R C677T genes. Results: We report on an indigenous Arabian population in the State of Qatar with a n estimated 1 in 5,000 incidence ofhomocystinuria. The sequencing data identified the presence o f homozygous c o m m o n R336C (c.1006C>T) missense m u t a t i o n in exon 9 of the CBS gene. Also patients were found to be heterozygous for ( M T H F R ) gene mutation C677T. Further mutation analysis o f 55 affected members of the same tribe confirmed the R336C as the prevalent CBS mutation. Conclusion: We have the highest incidence of the disease all over the world. Tiffs mutation is knovat as B6-nonresponsive patients that is severe mutation without residual activity and is associated with severe clinical phenotypes. Identification of this mutation will provide essential information for carrier testing, premarital counseling, prenatal diagnosis and early diagnosis of the disease in this population.
0205 A Novel O P A l mutation in a Fanfily with AutusOiilal Donfinant Optic Atrophy Federieo, A, Cardaioli, E, Galhis, G N , Malfatti, E, D a Pozzo, P, Franceschini, R, Caporossi, A, Dotti, MT. Dep.Neurological And
Behavioural Sciences, University Of Siena, Italy Heading: To identify pathogenic mutations in patients with A D O A , previously excluded for L H O N mutations. Background: Autosomal dominant optic atrophy (ADOA), Kjer type, is an inherited primary optic neuropathy that leads to reduced visual acuity. It presents with an insidious onset of variable visual loss, optic nerve pallor, centrocaecal visual field scotoma and colour vision deficit, t-Iistopathological studies suggest that the underlying defect is due to retinal ganglion cells degeneration, as found in Leber Hereditary Optic. Neuropathy (LHHON). Genetic linkage studies localized a dominant optic atrophy gene (OPAl; OMIMI65500) to chromosome 3q28ter. OPAl encodes a large GTPase related to dynanffns, implicated in the fomtafion a n d the maintenance of the mitochondrial network. Titus, A D O A seems to be due to intpaitment of the mitochondrial function. To date more than 70 mutations in about 250 A D O A patients have been reported in literature. Most of them (90%) are distributed from exons 8 to 28 with the majority in the GTPase domain. In particular almost 50% of the mutations are localized in exons 8, 9, 12 and 27. Methods: Genomic D N A was extracted fi'om leukocytes of two siblings with optic, atrophy. Exons 8, 9, 12 and 27 were amplified by polymerase chain reaction and directly sequenced. Results: One novel nonsense mutation was detected in exon 9, R312Stop, resulting from a C > T transition at position c.934. This sequence variation h a s n o t been previously reported. Conclusions: The exon 9 truncative m u t a t i o n found in this fanffly stress the importance to screen exons 8, 9, 12 and 27. The discovery of new mutations in O P A l leads us to concentrate our efforts on A D O A pathogenesis. The link between O P A l and apoptosis give clues of the possible pathophysiological effect of the m u t a t i o n that leads to neurodegeneration of the retinal ganglion cells. A full comprehension of tiffs mechanism could help us understanding L H O N pathogenesis. In conclusion, can Leber's and Kjer's diseases be considered variation on the same theme?
0206 Haplotype studies in sman ALS fanfilies: usefulness in tile search for new genes causing A L S