- Email: [email protected]
0282 ATP synthesis: the trigger between apoptosis and necrosis in patients with mitochondrial disorders
Poster Abstracts Results: A significant correlation was observed between skeletal muscle and M N C CoQlo concentration (r - 0.89, p < 0.02). The CoQI~ concentration of plasllra and skeletal llruscle (r - 0.015) and plasllra and MNC (r -- 0.21) were not found to correlate. Conclusions: The results of this study suggest that plasllra CoQ~0 status llray not reflect that of tissues such as skeletal muscle and therefore its use for the clinical evaluation of endogenous CoQ~o status may be limited. In contrast, M N C may be appropriate surrogates to assess tissue CoQ10 status. 0277 Rapidly Progressive Adult Hepatocerebral Degeneration & Pancreatitis secondary to 1399G-+A mutation in POLG1.
C.haila E ~, Walshe R 2, Donnelly M ~, McChiskey j2, Conlon K 2, Murphy R a, Howley R ~ & Farrell M 1. 1Beaumont Hospital, Dublin,
Ireland; 2The Adelaide & Meath Hospital, Ireland Background: Infantile Alpers or hepatopathic poliodystrophy is associated with mutations in POLG1, which encodes the catalytic subunit of mitochondrial D N A (MtDNA) polymerase. We report an adult with a 6-month illness characterised by acute pancreatitis, refractory seizures, subacate cortical blindness and hepatic failure ill whom sequencing o f POLG1 revealed tire 1 3 9 9 G ~ A mutation. Method: A 24-year-old llrall developed acute pallcreatitis with pseudocysts, followed by refractory focal motor seizures, with secondary generalisation resistant to anti-convulsants. Visual loss was associated with bilateral occipital M R hyperintensities. Persistent lrypoglycaellffa, elevated lactate and metabolic acidosis required dialysis. TermJllal hepatic failure was complicated by coagulopathy. Death occurred after 6 months. Results: Muscle biopsy demonstrated ragged red fibres; COX depletion and the common m t D N A 4977bp deletion. The occipital cortex showed neuronal loss; gliosis and spongiforrn change. The s.nigra, quadrigemillal plate, cerebellar cortex were also depleted of neurons and there was a sensory gallgliollopathy. There was hepatomegaly with macrovesicular and microvesicular fatty change and chronic pallcreatitis. Sequencing o f the POLGI gene demonstrated the 1399G--->A mutation in exon 7. Conclusion: Demonstration of a mutation in the POLG1 gene in an adult patient with Alpers' syndrome and tire 4977bp M t D N A common deletion expands the clinical and pathologic phellotype o f tiffs rare disorder. The profomrd therapeutic resistance to allti-epileptic drugs is reflective of disturbed drug metabolism possibly due to mitochondrial dysfunction. 0278 Prevalence of the MELAS A3243G Mutation in a large representative western population
Sue, C.M l, Jones, M M ~, Manwaring, N ~, Wang, j j2, Rochtchina, E ~, Howard, C 1, Mitchell, Pa. 1Kolling Institute, Department of Neuroge-
neties, University of Sydney, Australia; 2 Centre for Vision Research, Department of Ophthalmology, the Save Sight and Westmead Millennium Institutes, the University of Sydney, Australia Background: We aimed to detemrille the prevalence of the conmrollest mitochondrial D N A mutation (MELAS A3243G) in a large representative Western population. Method: We conducted a population-based cross-sectional survey of residents aged 49+ years living ill a suburban area of tire Blue Mountains, Sydney, Australia (ill - 3509). Total D N A was isolated from each subject's hair follicles and/or blood by standard laboratory techniques. M t D N A analysis to identify the MELAS A3243G point mutation was performed by polymerase chain reaction/restriction fragment length polymorphism analysis as previously described. Results: M t D N A fi'ollr either hair follicles or blood was available for 3377 o f tire 3509 BMES participants (96.2%). The MELAS A3243G point llmtatioll was identified ill seven mrrelated participants (16 male,
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1 female; ages 59-83; mean 70.1 years), giving a prevalence of 0.2% in this population. All had hearing loss (4 mild to moderate and 3 moderate to severe). One participant had diabetes, another participant had retinal pigmentary changes (classified as early age related macular degeneration) and none gave a history of stroke. No subject had been previously diagnosed as having mitocholldrial disease. Conehision: We found the prevalence of MELAS A3243G mutation to be 207/100 000 in this large population-based study. We believe that the MELAS A3243G mutation is markedly under-recognised in the collrmunity and its prevalence is likely to be similar to that of common neurological disorders. 0279 Multiple Symmetrical Lipomatosis: a clinical clue to the diagnosis of ulitochonflrial disease
Plmmller, C 1, Chill, j 1 Marotta, R 1, Berkovic, SF 2. 1St Vincent's
Hospital; Melbourne, Australia," 2AuMin Health, Melbourne, Australia Aim: To present a case series of Multiple Symmetrical Lipomatosis (MSL); and to emphasise that it serves as a clinical clue to the diagnosis of mitocholldrial disease. Background: MSL is a clinical diagnosis based on the presence of llollencapsulated axial lipomas. Plrellotypic variability of associated neurological abnormalities is striking and symptoms tend to be progressive. The pathogenesis is undefined but evidence implicates it as a disease of mitochondrial origin. Methods: Four patients were studied by clinical history, examination, and investigation (brain imaging, electroellcephalography, nerve conduction studies and electrollryography, llruscle biopsy and mitocholldrial D N A analysis). Results: All patients (three females, one male, age range 36-51) had cervical lipomas. They varied from subtle midiine lesions to large disfiguring masses. At presentation, three had proximal myopathy while llryoclollus, peripheral lleuropathy, and additional axial lipomas were variably present. All had muscle biopsies compatible with mitochondrial myopathy. Two were positive for the mitochondrial D N A A8344G point mutation; deletions were not identified. On follow up, all showed disease progression. Discussion: Tire series COllfirllrs tire phellotypic heterogeneity of MSL. Tire associated clinical findings include progressive llryoclonic epilepsy, severe ataxia, and llryopathy. There is histological and molecular genetic evidellce that MSL is a mitocholldrial cytopathy. Conehision: The clinical detection of MSL serves to flag the presence of mitochondrial disease and may explain otherwise puzzling neurological findings. 0280 A new sequence variant in ndtochondrial D N A associated with high penetrance of Russian Leber hereditary optic neuropathy
Povalko, N ~, Akita, Y~, Matsuishi, T 1, Koga, y1. 1R~rum e University
School of Medicine Background: Leber Hereditary Optic Neuropathy (LHON [MIM 535000]) is a llratemally inherited genetic disorder associated with point mutations in the rnitochondrial D N A (mtDNA) that cause blindness in young adults. It is characterized by incomplete penetrance and llrell are preferentially affected (~68%) when tire primary mutation of T14484C exist. We have 15 Russian L H O N patients frollr 13 unrelated Russian fallrilies, one of those showed 100% penetrance of the disease in men in that family. Method: Fifteen patients from 13 unrelated Russian families were fulfilled the clinical criteria of LHON. One family which has the highest penetrance among our 13 unrelated families showed 100% pelletrallce o f tire disease ill llrell o f maternal lineage. We have analyzed entire mJtocholldrial D N A sequence by direct sequence and PCR-RFLP analysis.
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Poster Abstracts
Monday, November 7, 2005
Results and conclusion: Seven patients from 5 unrelated families have one o f the primary mutations. This indexed family has a T14484C primary mutation, and 4 secondary mutations (T4216C, G13708A, G15812A, G15257A), which belong to the European haplogroup J. The new sequence variant of A9016G in the ATPase 6 gene changed highly conserved amino acid of isoleucine to valine, has not been found in the rest of 13 LHON patients and controls. This novel sequence variant may contribute to the 100% penetration of LHON disorder in men of this family. 0282 ATP synthesis: tile trigger between Apoptosis and Necrosis in paiients with Mitoehondtial disorders Shepherd, RK ~, Sue, CM a. 1Department of Neurogeneties, Kolling Institute of Medical Research, Royal North Shore Ho@ital and the University of Sydney, Sydney, Australia Background: Mitochondrial diseases can be associated with nmtations in both nuclear D N A (nDNA) and mitochondrial D N A (mtDNA). Mitochondrial disease is typically characterised by impaired respiratory chain function and reduced ATP synthesis. Respiratory chain dysfunction can lead to increased reactive oxygen species (ROS) production, which may lead to cell death via apoptosis or necrosis. The aim of tiffs study was to determine whether disturbances in ATP synthesis results in the cell becoming more susceptible to apoptotic or necrotic cell death following exposure to oxidative stress. Methods: ATP synthesis was measured in fibroblast cell lines from patients with m t D N A mutations (in - 8), n D N A mutations (in - 2) and control subjects (in - 7). Cell lines were also exposed to antimycin A for 2 hours. Cell death was characterised by acridine orange staining and fluorescent microscopy. Results: Patients with nDNA-encoded disorders had greater reductions in ATP synthesis compared to patients with mtDNA-encoded disorders. Nuclear condensation, indicative of apoptosis was observed in 29-51% (mean -- 42%) of cells in cultures derived from patients with m t D N A mutations, 21-26% (mean 24%) of cells in cultures derived from patients with n D N A defects and 26-49% (mean 37%) in control fibroblasts. Nuclear swelling indicative of necrosis was also observed in the cells derived from patients with n D N A defects. Conclusion: Fibroblasts with m t D N A mutations and mild reductions in ATP synthesis undergo apoptotic cell death pathways following exposure to oxidative stress. However, necrosis occurs in fibroblasts with n D N A defects and markedly reduced ATP synthesis. 0283 Apoptosis is Evident in Muscle Biopsies of Patients with Mitoehomirial Myopathy Tate, FY l, Brewer, j 2 Sue, CM i. 1Department of Neurology, Royal
North Shore Hospital and University of Sydney, Australia; 2Department of Anatomical Pathology, PALMS, Royal North Shore Hospital, Sydney, Australia Background: Mitochondrial myopathy (MM) is a muscle disease diagnosed by morphological changes in nluscle biopsies. The mechanisnl of nmscle degeneration is poorly understood, but apoptosis has been reported to be involved. Objective: To establish the presence of apoptotic changes in a large nunlber of patients with M M and to characterise the mechanism initiating cell death in affected muscle fibres. Method: hmnunotffstochemical studies were performed on muscle biopsies from 20 M M patients and 3 unaffected individuals. We used ten specific antibodies: F A D D (death receptor activation), B A x , and Phospho-Bcl-2, Bad, AIF, cytochrome c (mitochondrial involvement), active caspase-3, active caspase-8, caspase-12, and cleaved-PARP (nuclear involvement). Results: Cytoplasnffc expression of BAX, phospho-Bcl-2, BAD, cytochrome c, active caspase-3, cleaved-PARP, and AIF, indicative
of loss mitochondrial membrane potential and nuclear breakdown was observed. Caspase-12 positive fibres were observed in some patients (35%). All increase in F A D D expression was also observed in 50% of patients. Conclusion: Apoptosis is evident in nmscle biopsies o f patients with MM. Increased expression o f AIF and cleaved-PARP indicated that apoptosis was advanced. Upregulation of BAN, phospho-Bcl-2, and Bad indicated the loss of rnitochondrial membrane potential. High expression of caspase-12, implicated increased endoplasmic reticuhim (ER) stress in these patients. The mechanisms of cell death in M M patients may involve both caspase-dependent and caspase-independent pathways initiated by intrinsic, responses (such as ER stress, A I F release and Bcl-2 cleavage). Activation of both these pathways are likely to contribute to muscle degeneration in affected patients. 0285 Neuropsycllonletrie protiling in a case of Maternally inllerited diabetes and dealiless Vaithianathar L l, Vesey pa, Goddard A ~, Robson D.K a, Suri M 2, Bajaj
N a. 1 Queens Medical Centre, Nottingham, United Kingdom; 2City Hospital, Nottingham, United Kingdom Background: Neuropsychiatric symptoms have been reported in the mitochondrial disorder: maternally inherited diabetes and deafness (MIDD) but are not well characterised. Severe dementia has not been described. Case: We performed a cognitive evaluation and neuroimaging in a fourty-nine year old lady with M I D D (confimted by genetic testing and clinical criteria) who presented with an aggressive, recent onset denlentia. Decline in memory, language problems and poor concentration were reported over an eighteen-month period. The past medical history included recurrent miscarriages, bilateral sensorineural deafness, cardiac disease, pigmentary retinopathy, diabetes, hypothyroidism, migraine and neuromuscular weakness. There was a maternal fanffly history o f diabetes, deafness and cardiac disease. Results: Genetic testing demonstrated an A3243G point mutation in mitochondrial DNA. Her muscle biopsy was abnormal. Neuropsychometry showed a subnormal IQ. Language ability was relatively intact. Attention, working memory and speed of processing were poor. There was visual-perceptual and frontal executive dysfunction. Remote/semantic menlory was impaired. She had poor immediate and delayed recall o f new verbal information and poor recognition. Neuroimaging showed generalised atrophy, more marked in the right temporal lobe and normal spectroscopy. Discussion: Neuropsychological impaimlent Call be severe and global in MIDD, with a cortical rather than subcortical pattern of dementia. 0286 H I A typing in Saudi patients with illyasttletlia gravis AI Jumah, M l, Hajeer, A ~, AI Suwaidan, F a, Bohlegh, S2, AI Tahan, A ~, Cktpler, E ~. 1King Abdzdaziz Medical City, Riyadh,
Saudi Arabia; 2King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia; 3King KJlaled Ho@ital, King Saudi University Myasthelffa Gravis (MG) is all autoimmune disorder involving N M J receptors. Moderate association of M G with the human leukocyte antigen (HLA) system that are coded for by MCH genes has been described. M G associated with HLA system varies in different ethnic groups. Ill Caucasians, M G associated with tile HLA antigens B8, DR3 and DQW2, particularly in young females with thynffc hyperplasia. However, H L A association is different in Japanese and French patients. Pilot study in Saudi M G patients suggested association with HLA DQ5 and B18. Objectives: To study the association of M G with HLA antigen in Saudis. Methods: Ninety three (193) patients fi'om different fanfflies with confirmed diagnosis of M G and 100 nomlal controls were involved in
C.haila E ~, Walshe R 2, Donnelly M ~, McChiskey j2, Conlon K 2, Murphy R a, Howley R ~ & Farrell M 1. 1Beaumont Hospital, Dublin,
Ireland; 2The Adelaide & Meath Hospital, Ireland Background: Infantile Alpers or hepatopathic poliodystrophy is associated with mutations in POLG1, which encodes the catalytic subunit of mitochondrial D N A (MtDNA) polymerase. We report an adult with a 6-month illness characterised by acute pancreatitis, refractory seizures, subacate cortical blindness and hepatic failure ill whom sequencing o f POLG1 revealed tire 1 3 9 9 G ~ A mutation. Method: A 24-year-old llrall developed acute pallcreatitis with pseudocysts, followed by refractory focal motor seizures, with secondary generalisation resistant to anti-convulsants. Visual loss was associated with bilateral occipital M R hyperintensities. Persistent lrypoglycaellffa, elevated lactate and metabolic acidosis required dialysis. TermJllal hepatic failure was complicated by coagulopathy. Death occurred after 6 months. Results: Muscle biopsy demonstrated ragged red fibres; COX depletion and the common m t D N A 4977bp deletion. The occipital cortex showed neuronal loss; gliosis and spongiforrn change. The s.nigra, quadrigemillal plate, cerebellar cortex were also depleted of neurons and there was a sensory gallgliollopathy. There was hepatomegaly with macrovesicular and microvesicular fatty change and chronic pallcreatitis. Sequencing o f the POLGI gene demonstrated the 1399G--->A mutation in exon 7. Conclusion: Demonstration of a mutation in the POLG1 gene in an adult patient with Alpers' syndrome and tire 4977bp M t D N A common deletion expands the clinical and pathologic phellotype o f tiffs rare disorder. The profomrd therapeutic resistance to allti-epileptic drugs is reflective of disturbed drug metabolism possibly due to mitochondrial dysfunction. 0278 Prevalence of the MELAS A3243G Mutation in a large representative western population
Sue, C.M l, Jones, M M ~, Manwaring, N ~, Wang, j j2, Rochtchina, E ~, Howard, C 1, Mitchell, Pa. 1Kolling Institute, Department of Neuroge-
neties, University of Sydney, Australia; 2 Centre for Vision Research, Department of Ophthalmology, the Save Sight and Westmead Millennium Institutes, the University of Sydney, Australia Background: We aimed to detemrille the prevalence of the conmrollest mitochondrial D N A mutation (MELAS A3243G) in a large representative Western population. Method: We conducted a population-based cross-sectional survey of residents aged 49+ years living ill a suburban area of tire Blue Mountains, Sydney, Australia (ill - 3509). Total D N A was isolated from each subject's hair follicles and/or blood by standard laboratory techniques. M t D N A analysis to identify the MELAS A3243G point mutation was performed by polymerase chain reaction/restriction fragment length polymorphism analysis as previously described. Results: M t D N A fi'ollr either hair follicles or blood was available for 3377 o f tire 3509 BMES participants (96.2%). The MELAS A3243G point llmtatioll was identified ill seven mrrelated participants (16 male,
Monday, November 7, 2005
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1 female; ages 59-83; mean 70.1 years), giving a prevalence of 0.2% in this population. All had hearing loss (4 mild to moderate and 3 moderate to severe). One participant had diabetes, another participant had retinal pigmentary changes (classified as early age related macular degeneration) and none gave a history of stroke. No subject had been previously diagnosed as having mitocholldrial disease. Conehision: We found the prevalence of MELAS A3243G mutation to be 207/100 000 in this large population-based study. We believe that the MELAS A3243G mutation is markedly under-recognised in the collrmunity and its prevalence is likely to be similar to that of common neurological disorders. 0279 Multiple Symmetrical Lipomatosis: a clinical clue to the diagnosis of ulitochonflrial disease
Plmmller, C 1, Chill, j 1 Marotta, R 1, Berkovic, SF 2. 1St Vincent's
Hospital; Melbourne, Australia," 2AuMin Health, Melbourne, Australia Aim: To present a case series of Multiple Symmetrical Lipomatosis (MSL); and to emphasise that it serves as a clinical clue to the diagnosis of mitocholldrial disease. Background: MSL is a clinical diagnosis based on the presence of llollencapsulated axial lipomas. Plrellotypic variability of associated neurological abnormalities is striking and symptoms tend to be progressive. The pathogenesis is undefined but evidence implicates it as a disease of mitochondrial origin. Methods: Four patients were studied by clinical history, examination, and investigation (brain imaging, electroellcephalography, nerve conduction studies and electrollryography, llruscle biopsy and mitocholldrial D N A analysis). Results: All patients (three females, one male, age range 36-51) had cervical lipomas. They varied from subtle midiine lesions to large disfiguring masses. At presentation, three had proximal myopathy while llryoclollus, peripheral lleuropathy, and additional axial lipomas were variably present. All had muscle biopsies compatible with mitochondrial myopathy. Two were positive for the mitochondrial D N A A8344G point mutation; deletions were not identified. On follow up, all showed disease progression. Discussion: Tire series COllfirllrs tire phellotypic heterogeneity of MSL. Tire associated clinical findings include progressive llryoclonic epilepsy, severe ataxia, and llryopathy. There is histological and molecular genetic evidellce that MSL is a mitocholldrial cytopathy. Conehision: The clinical detection of MSL serves to flag the presence of mitochondrial disease and may explain otherwise puzzling neurological findings. 0280 A new sequence variant in ndtochondrial D N A associated with high penetrance of Russian Leber hereditary optic neuropathy
Povalko, N ~, Akita, Y~, Matsuishi, T 1, Koga, y1. 1R~rum e University
School of Medicine Background: Leber Hereditary Optic Neuropathy (LHON [MIM 535000]) is a llratemally inherited genetic disorder associated with point mutations in the rnitochondrial D N A (mtDNA) that cause blindness in young adults. It is characterized by incomplete penetrance and llrell are preferentially affected (~68%) when tire primary mutation of T14484C exist. We have 15 Russian L H O N patients frollr 13 unrelated Russian fallrilies, one of those showed 100% penetrance of the disease in men in that family. Method: Fifteen patients from 13 unrelated Russian families were fulfilled the clinical criteria of LHON. One family which has the highest penetrance among our 13 unrelated families showed 100% pelletrallce o f tire disease ill llrell o f maternal lineage. We have analyzed entire mJtocholldrial D N A sequence by direct sequence and PCR-RFLP analysis.
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Poster Abstracts
Monday, November 7, 2005
Results and conclusion: Seven patients from 5 unrelated families have one o f the primary mutations. This indexed family has a T14484C primary mutation, and 4 secondary mutations (T4216C, G13708A, G15812A, G15257A), which belong to the European haplogroup J. The new sequence variant of A9016G in the ATPase 6 gene changed highly conserved amino acid of isoleucine to valine, has not been found in the rest of 13 LHON patients and controls. This novel sequence variant may contribute to the 100% penetration of LHON disorder in men of this family. 0282 ATP synthesis: tile trigger between Apoptosis and Necrosis in paiients with Mitoehondtial disorders Shepherd, RK ~, Sue, CM a. 1Department of Neurogeneties, Kolling Institute of Medical Research, Royal North Shore Ho@ital and the University of Sydney, Sydney, Australia Background: Mitochondrial diseases can be associated with nmtations in both nuclear D N A (nDNA) and mitochondrial D N A (mtDNA). Mitochondrial disease is typically characterised by impaired respiratory chain function and reduced ATP synthesis. Respiratory chain dysfunction can lead to increased reactive oxygen species (ROS) production, which may lead to cell death via apoptosis or necrosis. The aim of tiffs study was to determine whether disturbances in ATP synthesis results in the cell becoming more susceptible to apoptotic or necrotic cell death following exposure to oxidative stress. Methods: ATP synthesis was measured in fibroblast cell lines from patients with m t D N A mutations (in - 8), n D N A mutations (in - 2) and control subjects (in - 7). Cell lines were also exposed to antimycin A for 2 hours. Cell death was characterised by acridine orange staining and fluorescent microscopy. Results: Patients with nDNA-encoded disorders had greater reductions in ATP synthesis compared to patients with mtDNA-encoded disorders. Nuclear condensation, indicative of apoptosis was observed in 29-51% (mean -- 42%) of cells in cultures derived from patients with m t D N A mutations, 21-26% (mean 24%) of cells in cultures derived from patients with n D N A defects and 26-49% (mean 37%) in control fibroblasts. Nuclear swelling indicative of necrosis was also observed in the cells derived from patients with n D N A defects. Conclusion: Fibroblasts with m t D N A mutations and mild reductions in ATP synthesis undergo apoptotic cell death pathways following exposure to oxidative stress. However, necrosis occurs in fibroblasts with n D N A defects and markedly reduced ATP synthesis. 0283 Apoptosis is Evident in Muscle Biopsies of Patients with Mitoehomirial Myopathy Tate, FY l, Brewer, j 2 Sue, CM i. 1Department of Neurology, Royal
North Shore Hospital and University of Sydney, Australia; 2Department of Anatomical Pathology, PALMS, Royal North Shore Hospital, Sydney, Australia Background: Mitochondrial myopathy (MM) is a muscle disease diagnosed by morphological changes in nluscle biopsies. The mechanisnl of nmscle degeneration is poorly understood, but apoptosis has been reported to be involved. Objective: To establish the presence of apoptotic changes in a large nunlber of patients with M M and to characterise the mechanism initiating cell death in affected muscle fibres. Method: hmnunotffstochemical studies were performed on muscle biopsies from 20 M M patients and 3 unaffected individuals. We used ten specific antibodies: F A D D (death receptor activation), B A x , and Phospho-Bcl-2, Bad, AIF, cytochrome c (mitochondrial involvement), active caspase-3, active caspase-8, caspase-12, and cleaved-PARP (nuclear involvement). Results: Cytoplasnffc expression of BAX, phospho-Bcl-2, BAD, cytochrome c, active caspase-3, cleaved-PARP, and AIF, indicative
of loss mitochondrial membrane potential and nuclear breakdown was observed. Caspase-12 positive fibres were observed in some patients (35%). All increase in F A D D expression was also observed in 50% of patients. Conclusion: Apoptosis is evident in nmscle biopsies o f patients with MM. Increased expression o f AIF and cleaved-PARP indicated that apoptosis was advanced. Upregulation of BAN, phospho-Bcl-2, and Bad indicated the loss of rnitochondrial membrane potential. High expression of caspase-12, implicated increased endoplasmic reticuhim (ER) stress in these patients. The mechanisms of cell death in M M patients may involve both caspase-dependent and caspase-independent pathways initiated by intrinsic, responses (such as ER stress, A I F release and Bcl-2 cleavage). Activation of both these pathways are likely to contribute to muscle degeneration in affected patients. 0285 Neuropsycllonletrie protiling in a case of Maternally inllerited diabetes and dealiless Vaithianathar L l, Vesey pa, Goddard A ~, Robson D.K a, Suri M 2, Bajaj
N a. 1 Queens Medical Centre, Nottingham, United Kingdom; 2City Hospital, Nottingham, United Kingdom Background: Neuropsychiatric symptoms have been reported in the mitochondrial disorder: maternally inherited diabetes and deafness (MIDD) but are not well characterised. Severe dementia has not been described. Case: We performed a cognitive evaluation and neuroimaging in a fourty-nine year old lady with M I D D (confimted by genetic testing and clinical criteria) who presented with an aggressive, recent onset denlentia. Decline in memory, language problems and poor concentration were reported over an eighteen-month period. The past medical history included recurrent miscarriages, bilateral sensorineural deafness, cardiac disease, pigmentary retinopathy, diabetes, hypothyroidism, migraine and neuromuscular weakness. There was a maternal fanffly history o f diabetes, deafness and cardiac disease. Results: Genetic testing demonstrated an A3243G point mutation in mitochondrial DNA. Her muscle biopsy was abnormal. Neuropsychometry showed a subnormal IQ. Language ability was relatively intact. Attention, working memory and speed of processing were poor. There was visual-perceptual and frontal executive dysfunction. Remote/semantic menlory was impaired. She had poor immediate and delayed recall o f new verbal information and poor recognition. Neuroimaging showed generalised atrophy, more marked in the right temporal lobe and normal spectroscopy. Discussion: Neuropsychological impaimlent Call be severe and global in MIDD, with a cortical rather than subcortical pattern of dementia. 0286 H I A typing in Saudi patients with illyasttletlia gravis AI Jumah, M l, Hajeer, A ~, AI Suwaidan, F a, Bohlegh, S2, AI Tahan, A ~, Cktpler, E ~. 1King Abdzdaziz Medical City, Riyadh,
Saudi Arabia; 2King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia; 3King KJlaled Ho@ital, King Saudi University Myasthelffa Gravis (MG) is all autoimmune disorder involving N M J receptors. Moderate association of M G with the human leukocyte antigen (HLA) system that are coded for by MCH genes has been described. M G associated with HLA system varies in different ethnic groups. Ill Caucasians, M G associated with tile HLA antigens B8, DR3 and DQW2, particularly in young females with thynffc hyperplasia. However, H L A association is different in Japanese and French patients. Pilot study in Saudi M G patients suggested association with HLA DQ5 and B18. Objectives: To study the association of M G with HLA antigen in Saudis. Methods: Ninety three (193) patients fi'om different fanfflies with confirmed diagnosis of M G and 100 nomlal controls were involved in