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Immunohistochemical studies of muscle and nerve in merosin-deficient congenital muscular dystrophy
S18 DO2
EIS 1
Immunohistochemical studies of muscle and nerve in Merosin-deficient Congenital Muscular Dystrophy
DOES MYOTONIC DYSTROPHY HAVE A D E V E L O P M E N T A L B A S I S A N D IS I T A S I N G L E GENE DISORDER?
C. Piantadosi, S. Servidei, E. Bertini, A. Broccolini, E. Ricci, A. Spinazzola, G. Silvestri, P. Tonali. Institute of Neurology, Catholic University and U.I.L.D.M.- Rome Recently it has been shown that merosin, a newly discovered laminin, is absent in muscle of some patients with "pure" form of congenital muscular dystrophy (CMD). Merosin is linked to dystrophin-associated glycoproteins (DAG) and is a component of basement membrane (BM) of muscle, heart, Schwann sheath and placenta. Leukoencephalopathy and nerve slow conduction have been described in some patients with merosin-deficient CMD, but the role of merosin in the myelination process is still undefined. We studied two merosin-negative patients, 4 mo and 12 ys old, showing marked muscle weakness and early contractures. Brain MR/disclosed severe leukodystrophy, but peripheral sensory and motor nerve conduction was normal in both patients. Muscle morphology revealed marked endomisial fibrosis and large infiltrates of inflammatory-like cells. We studied merosin, dystrophin, 43 DAG, 50 DAG, a6 and 131 integrins and heparan sulfate proteoglycan (HSPG) in muscle and intramuscular nerves. Merosin was absent, while HSPG and integrins were normal in muscle and nerves. Intramuscular nerves did not show demyelination, and Schwann cells and perineurium, although lacking merosin, had good expression of a6 and 131 integrins. Conclusions: 1) peripheral demyelination is not a feature of our CMD patients; 2) marked fibrosis and infiltrates are present both at early stage (4 months) and late stage (12 ys); 3) CMD may be a formative collagene disease and early infiltrates could play a role. Supported by U.I.L.D.M. of Rome and Telethon - Italy
EIS2 GENOTYPE-PHENOTYPE RELATIONSHIPS IN MYOTONIC DYSTROPHY A n t o n i o Pizzuti, M,D.,Ph.D. Istituto di Clinica Neurologica, Universita' di Milano, Centro "Dino Ferrari" M y o t o n i c D y s t r o p h y (DM) is c a u s e d b y i n s t a b i l i t y o f a n AGC r e p e a t , in a p r o t e i n k i n a s e g e n e . DM e x h i b i t s e x p r e s s i o n v a r i a b i l i t y , e v e n in t h e s a m e f a m i l y , a n d c l i n i c a l a n t i c i p a t i o n . G e n e t i c d i a g n o s i s is p e r f o r m e d m e a s u r i n g t h e triplet repeat length by Southern blotting a n d / o r PCR, N o r m a l a l l e l e s c o n t a i n f r o m 5 to a b o u t 50 AGCs, W h e n m o r e t h a n 5 0 t r i p l e t s a r e p r e s e n t t h e r e s u l t is DM. D i f f e r e n c e s in r e p e a t length account for differences in disease severity. Progressive repeat length increase trough generations is t h e b a s i s o f t h e anticipation phenomenon. In g e n e r a l , t h e longer the repeat the most severe the disease. The direct repeat length/severity relation g i v e s a c h a n c e to a s s i g n a p r e d i c t i n g v a l u e to t h e g e n e t i c a n a l y s i s i n DM, m o s t i m p o r t a n t i n prenatal testing. However, the DM genotype does not always predict the phenotype. The origin of discrepancies may the somatic mosaicism DM patients show regarding the triplet length.
Johnson, KJ, Boueher, CA, King, SK 1, Winchester, CL, Bailey, MES and Carey, N 1 Division of Molecular Genetics, Anderson College, University of Glasgow, 56 Dumbarton Road, Glasgow Gll 6NU, IDeparanents of Anatomy and Biochemistry, Chafing Cross and Westminster Medical School, Fulham Palace Road, London W6 8RF The commonest cause of adult muscular dystrophy is myotonic dystrophy (DM) which is inherited as an autosomai dominant trait and is associated with a (CTG)n repeat expansion on chromos~ne 19q13.3, The repeat occurs in a region of the human genome which is particularly gene rich and directly impinges on at least two transcription units. The (CTG)n is located in the 3'-antranslated region of a protein kinase encoding gene (DMPK), so that it is trmaseribed but not translated. It also interrupts a DNA dement known as a CpG island which contains promoter elements of a gene encoding a homenbox containing transcription factor, which we have named DM associated homeodomain protein (DMAHP). The DM phenotype may be due to the simultaneous disruption of the function of these two gane products in some tissues which express both genes and to single gene dysfunction in others. The genotypophenotype relationships in DM are further complicated by the remarkable tissue heterogeneity of the repeat expansion. This is added to by the probable spreading of the effect of the mutation into other neighbouring transcription units through perturbations of the chromatin structure (field effect). Thus DM is likely to turn out to be one of the most complex Mendelian traits in relation to its underlying pathophysiological mechanisms, but also one of the most fascinating to study.
EP1
HOW IS S O M N O L E N C E I N M Y O T O N I C DYSTROPHY RELATED TO OTHER A S P E C T S OF THE DISORDER ? M.F.PhillipsI, J.R. SoidanI, H.M.Steer1, C.M.Wiles 2, P.S.Harper I. Institute of Medical Genetics I and Department of Medicine (Neurology) 2, University of Wales College of Medicine, Heath Park, C a r ~ , Wales, CF4 4XN. Somnolence has been thought to be associated with myotonic dystrophy (DM) for many years. However this has not been shown using a previously validated daytime somnolence scale and the relationship with the many different factors which could plausibly contribute to it have not been explored in a controlled study. We investigated 43 subjects with adult onset DM, 13 controls with Charcot Marie Tooth (CMT) disease (as a group with peripheral neuromuscular weakness but no central componen0, and 17 controls unaffected by neuromuscular disease. The Epworth Sleepiness Scale (ESS) was used to measure daytime somnolence. Night-time sleep and the possible contributory factors of ventilatory function, disability, depression, central respiral~ry control and central arousal mechanisms were measured using appropriate indices. The results showed a significant difference in daytime sleepiness between DM patients and unaffected controls, but not between the former and CMT controls. However, DM patients showed a greater degree of clinically significant sleepiness (ie: an ESS score > 16). Correlations within the DM group and the relationship between DM and control groups are discussed with reference to their possible relevance to causes, and hence management, of somnolence in myotonic dystrophy.
EIS 1
Immunohistochemical studies of muscle and nerve in Merosin-deficient Congenital Muscular Dystrophy
DOES MYOTONIC DYSTROPHY HAVE A D E V E L O P M E N T A L B A S I S A N D IS I T A S I N G L E GENE DISORDER?
C. Piantadosi, S. Servidei, E. Bertini, A. Broccolini, E. Ricci, A. Spinazzola, G. Silvestri, P. Tonali. Institute of Neurology, Catholic University and U.I.L.D.M.- Rome Recently it has been shown that merosin, a newly discovered laminin, is absent in muscle of some patients with "pure" form of congenital muscular dystrophy (CMD). Merosin is linked to dystrophin-associated glycoproteins (DAG) and is a component of basement membrane (BM) of muscle, heart, Schwann sheath and placenta. Leukoencephalopathy and nerve slow conduction have been described in some patients with merosin-deficient CMD, but the role of merosin in the myelination process is still undefined. We studied two merosin-negative patients, 4 mo and 12 ys old, showing marked muscle weakness and early contractures. Brain MR/disclosed severe leukodystrophy, but peripheral sensory and motor nerve conduction was normal in both patients. Muscle morphology revealed marked endomisial fibrosis and large infiltrates of inflammatory-like cells. We studied merosin, dystrophin, 43 DAG, 50 DAG, a6 and 131 integrins and heparan sulfate proteoglycan (HSPG) in muscle and intramuscular nerves. Merosin was absent, while HSPG and integrins were normal in muscle and nerves. Intramuscular nerves did not show demyelination, and Schwann cells and perineurium, although lacking merosin, had good expression of a6 and 131 integrins. Conclusions: 1) peripheral demyelination is not a feature of our CMD patients; 2) marked fibrosis and infiltrates are present both at early stage (4 months) and late stage (12 ys); 3) CMD may be a formative collagene disease and early infiltrates could play a role. Supported by U.I.L.D.M. of Rome and Telethon - Italy
EIS2 GENOTYPE-PHENOTYPE RELATIONSHIPS IN MYOTONIC DYSTROPHY A n t o n i o Pizzuti, M,D.,Ph.D. Istituto di Clinica Neurologica, Universita' di Milano, Centro "Dino Ferrari" M y o t o n i c D y s t r o p h y (DM) is c a u s e d b y i n s t a b i l i t y o f a n AGC r e p e a t , in a p r o t e i n k i n a s e g e n e . DM e x h i b i t s e x p r e s s i o n v a r i a b i l i t y , e v e n in t h e s a m e f a m i l y , a n d c l i n i c a l a n t i c i p a t i o n . G e n e t i c d i a g n o s i s is p e r f o r m e d m e a s u r i n g t h e triplet repeat length by Southern blotting a n d / o r PCR, N o r m a l a l l e l e s c o n t a i n f r o m 5 to a b o u t 50 AGCs, W h e n m o r e t h a n 5 0 t r i p l e t s a r e p r e s e n t t h e r e s u l t is DM. D i f f e r e n c e s in r e p e a t length account for differences in disease severity. Progressive repeat length increase trough generations is t h e b a s i s o f t h e anticipation phenomenon. In g e n e r a l , t h e longer the repeat the most severe the disease. The direct repeat length/severity relation g i v e s a c h a n c e to a s s i g n a p r e d i c t i n g v a l u e to t h e g e n e t i c a n a l y s i s i n DM, m o s t i m p o r t a n t i n prenatal testing. However, the DM genotype does not always predict the phenotype. The origin of discrepancies may the somatic mosaicism DM patients show regarding the triplet length.
Johnson, KJ, Boueher, CA, King, SK 1, Winchester, CL, Bailey, MES and Carey, N 1 Division of Molecular Genetics, Anderson College, University of Glasgow, 56 Dumbarton Road, Glasgow Gll 6NU, IDeparanents of Anatomy and Biochemistry, Chafing Cross and Westminster Medical School, Fulham Palace Road, London W6 8RF The commonest cause of adult muscular dystrophy is myotonic dystrophy (DM) which is inherited as an autosomai dominant trait and is associated with a (CTG)n repeat expansion on chromos~ne 19q13.3, The repeat occurs in a region of the human genome which is particularly gene rich and directly impinges on at least two transcription units. The (CTG)n is located in the 3'-antranslated region of a protein kinase encoding gene (DMPK), so that it is trmaseribed but not translated. It also interrupts a DNA dement known as a CpG island which contains promoter elements of a gene encoding a homenbox containing transcription factor, which we have named DM associated homeodomain protein (DMAHP). The DM phenotype may be due to the simultaneous disruption of the function of these two gane products in some tissues which express both genes and to single gene dysfunction in others. The genotypophenotype relationships in DM are further complicated by the remarkable tissue heterogeneity of the repeat expansion. This is added to by the probable spreading of the effect of the mutation into other neighbouring transcription units through perturbations of the chromatin structure (field effect). Thus DM is likely to turn out to be one of the most complex Mendelian traits in relation to its underlying pathophysiological mechanisms, but also one of the most fascinating to study.
EP1
HOW IS S O M N O L E N C E I N M Y O T O N I C DYSTROPHY RELATED TO OTHER A S P E C T S OF THE DISORDER ? M.F.PhillipsI, J.R. SoidanI, H.M.Steer1, C.M.Wiles 2, P.S.Harper I. Institute of Medical Genetics I and Department of Medicine (Neurology) 2, University of Wales College of Medicine, Heath Park, C a r ~ , Wales, CF4 4XN. Somnolence has been thought to be associated with myotonic dystrophy (DM) for many years. However this has not been shown using a previously validated daytime somnolence scale and the relationship with the many different factors which could plausibly contribute to it have not been explored in a controlled study. We investigated 43 subjects with adult onset DM, 13 controls with Charcot Marie Tooth (CMT) disease (as a group with peripheral neuromuscular weakness but no central componen0, and 17 controls unaffected by neuromuscular disease. The Epworth Sleepiness Scale (ESS) was used to measure daytime somnolence. Night-time sleep and the possible contributory factors of ventilatory function, disability, depression, central respiral~ry control and central arousal mechanisms were measured using appropriate indices. The results showed a significant difference in daytime sleepiness between DM patients and unaffected controls, but not between the former and CMT controls. However, DM patients showed a greater degree of clinically significant sleepiness (ie: an ESS score > 16). Correlations within the DM group and the relationship between DM and control groups are discussed with reference to their possible relevance to causes, and hence management, of somnolence in myotonic dystrophy.