using-whole-mount-immunohistochemical-method-to-study-innervation

Using a Whole-mount Immunohistochemical Method to Study the Innervation of the Biliary Tract in <em>Suncus murinus</em>

This work describes the whole-mount immunohistochemistry staining method in detail, using neurofilament protein antibody to label the innervation of the ...

Tokyo Metropolitan University

We examined (CTG)n lengths in various tissues from a 70-year-old man with myotonic dystrophy type 1 (DM 1) who had a small 60-70 (CTG), expansion in his leukocytes. He died of renal cell carcinoma 5 years after a total laryngectomy for laryngeal carcinoma. Southern blot and polymerase chain reaction analyses were done on tissues obtained at autopsy. In the various normal tissues, (CTG). lengths were almost all the same size, whereas the renal cell carcinoma and metastatic tissues had longer lengths. When compared with the lengths in leukocytes about 5 years previously, (CTG)n lengths in the normal tissues were the same size. These findings suggest that both somatic instability and age-dependent (CTG). expansion in DM 1 patients with a small expansion may be less dominant than in patients with large expansions.

A patient with myotonic dystrophy type 1 (DM 1) accompanied by laryngeal and renal cell carcinomas had a small CTG triplet repeat expansion but no somatic instability in normal tissues.

A 37-year-old Japanese woman was referred from another clinic to confirm the diagnosis of myotonia congenita. She had experienced cold-induced myotonia and muscle stiffness from early childhood. Of her three children, her elder son and her daughter have clinical features similar to hers. They experience neither grip nor percussion myotonia during warm weather, whereas myotonia is provoked by cold. Her younger son has no symptoms. DNA analyses of the SCN4A gene showed a C to T transition at nucleotide position 3938 in exon 22 of SCN4A (Thr1313Met) in all three affected family members, but not in the unaffected son. Paramyotonia congenita, the prevalence of which is very low in Japan, was diagnosed based on their clinical features and DNA analysis results.

Thr1313Met mutation in skeletal muscle sodium channels in a Japanese family with paramyotonia congenita.

[Severe hypocalcemia compatible with idiopathic hypoparathyroidism associated with psoriasis vulgaris].

No definite sign was found of central oculomotor system disorders being independent of saccadic slowing because (1) diminished maximum slow phase velocity of the optokinetic nystagmus (OKNspv) was closely related to saccadic slowing (p<0.01, r=0.59), (2) maximum frequency of optokinetic nystagmus (OKNfq) was normal, (3) visual suppression (VS) change was mild, and (4) the diminished maximum slow phase velocity of the caloric nystagmus (CNspv) seen in some patients is explained by both peripheral and central vestibular involvement. These findings support the extraocular muscle hypothesis.

Eye movement disorders in myotonic dystrophy type 1.

Myotonia &#x5728;&#x51E0;&#x79CD;&#x9057;&#x4F20;&#x6027;&#x75BE;&#x75C5;&#xFF0C;&#x5305;&#x62EC;&#x9AD8;&#x8840;&#x94BE;&#x5468;&#x671F;&#x6027;&#x9EBB;&#x75F9; (HyperPP)&#x3001; paramyotonia &#x2171; (PMC) &#x548C;&#x94BE;&#x52A0;&#x91CD; myotonia (PAM) &#x4E2D;&#x4F53;&#x73B0;&#x3002;&#x8FD9;&#x4E9B;&#x90FD;&#x662F;&#x6E90;&#x81EA;&#x7801;&#x9AA8;&#x9ABC;&#x808C;&#x7EC6;&#x80DE;&#x94A0;&#x901A;&#x9053;&#xFF0C;Nav1.4 &#x7684;&#x57FA;&#x56E0;&#x9519;&#x4E49;&#x7A81;&#x53D8;&#x7684;&#x7B49;&#x4F4D;&#x57FA;&#x56E0;&#x75BE;&#x75C5;&#x3002;&#x6B64;&#x5916;&#xFF0C;&#x4E00;&#x79CD;&#x4E25;&#x91CD;&#x7684; PAM &#x5F62;&#x5F0F;&#x5DF2;&#x88AB;&#x6307;&#x5B9A;&#x4E3A; myotonia permanens&#x3002;&#x65B0;&#x7684;&#x53D8;&#x5F02;&#x682A; Nav1.4&#xFF0C;Q1633E&#xFF0C;&#x88AB;&#x786E;&#x5B9A;&#x5728;&#x4E0E; PAM &#x8868;&#x578B;&#x7684;&#x65E5;&#x672C;&#x5BB6;&#x5EAD;&#x4ECB;&#x7ECD;&#x3002;&#x5148;&#x8BC1;&#x8005;&#x906D;&#x53D7;&#x7D2B;&#x7EC0;&#x653B;&#x51FB;&#x5728;&#x5A74;&#x513F;&#x671F;&#x3002;&#x7A81;&#x53D8;&#x7684;&#x6C28;&#x57FA;&#x9178;&#x6B8B;&#x57FA;&#x4F4D;&#x4E8E;&#x7EC6;&#x80DE;&#x5185;&#x7684; C &#x603B;&#x7AD9;&#x7684; EF &#x624B;&#x9499;&#x7ED3;&#x5408;&#x4E3B;&#x9898;&#x4E0A;&#x3002;&#x4F7F;&#x7528;&#x7535;&#x538B;&#x94B3;&#x6CD5;&#x7684;&#x7A81;&#x53D8;&#x4F53;&#x901A;&#x9053;&#x7684;&#x529F;&#x80FD;&#x5206;&#x6790;&#x4E2D;&#x7684;&#x53EF;&#x7528;&#x6027;&#x7684;&#x7535;&#x538B;&#x4F9D;&#x8D56;&#x900F;&#x9732;&#x7684;&#x4E2D;&#x65AD;&#x5FEB;&#x901F;&#x706D;&#x6D3B;&#x3001; &#x7535;&#x6D41;&#x8870;&#x51CF;&#x7684;&#x901F;&#x5EA6;&#x653E;&#x6162;&#x548C;&#x6D88;&#x504F;&#x578B;&#x7684;&#x8F6C;&#x53D8;&#x3002;&#x8FD9;&#x9879;&#x7814;&#x7A76;&#x786E;&#x5B9A;&#x4E86; PAM &#x7684;&#x65B0;&#x53D8;&#x5F02;&#x682A;&#x4E0E;&#x4E25;&#x91CD;&#x7684;&#x8868;&#x578B;&#x548C;&#x5F3A;&#x8C03;&#x7684;&#x94A0;&#x901A;&#x9053;&#x5FEB;&#x901F;&#x706D;&#x6D3B; C &#x603B;&#x7AD9;&#x7684;&#x91CD;&#x8981;&#x6027;&#x3002;&#x808C;&#x8089;&#x795E;&#x7ECF; 39&#xFF1A; 666-673&#xFF0C;2009&#x5E74;&#x3002;

&#x65B0;&#x7A81;&#x53D8;&#x7684;&#x4E25;&#x91CD;&#x5F62;&#x5F0F;&#x7684;&#x94BE;&#x52A0;&#x91CD; myotonia Na &#x901A;&#x9053;&#x3002;

Myotonia manifests in several hereditary diseases, including hyperkalemic periodic paralysis (HyperPP), paramyotonia congenita (PMC), and potassium-aggravated myotonia (PAM). These are allelic disorders originating from missense mutations in the gene that codes the skeletal muscle sodium channel, Nav1.4. Moreover, a severe form of PAM has been designated as myotonia permanens. A new mutation of Nav1.4, Q1633E, was identified in a Japanese family presenting with the PAM phenotype. The proband suffered from cyanotic attacks during infancy. The mutated amino acid residue is located on the EF-hand calcium-binding motif in the intracellular C-terminus. A functional analysis of the mutant channel using the voltage-clamp method revealed disruption of fast inactivation, a slower rate of current decay, and a depolarized shift in the voltage dependence of availability. This study has identified a new mutation of PAM with a severe phenotype and emphasizes the importance of the C-terminus for fast inactivation of the sodium channel. Muscle Nerve 39: 666-673, 2009.

New mutation of the Na channel in the severe form of potassium-aggravated myotonia.

Myotonie se manifeste dans plusieurs maladies h&eacute;r&eacute;ditaires, y compris la paralysie p&eacute;riodique de hyperkalemic (HyperPP), congenita de paramyotonia (PMC) et myotonie aggrav&eacute;e de potassium (PAM). Voici les maladies all&eacute;liques provenant des mutations faux-sens du g&egrave;ne codant le canal sodique de muscle squelettique, Nav1.4. En outre, une forme grave du PAM a &eacute;t&eacute; d&eacute;sign&eacute;e comme myotonie permanens. Une nouvelle mutation de Nav1.4, Q1633E, a &eacute;t&eacute; identifi&eacute;e dans une famille japonaise pr&eacute;sentant le ph&eacute;notype du PAM. Le proband souffrait d&#39;attaques cyanotique pendant la petite enfance. Le r&eacute;sidu mut&eacute; d&#39;acides amin&eacute;s se trouve sur le motif de liaison du calcium EF-main dans la partie C-terminale intracellulaire. Une analyse fonctionnelle de la cha&icirc;ne de mutante &agrave; l&#39;aide de la m&eacute;thode de voltage clamp a r&eacute;v&eacute;l&eacute; perturbation d&#39;inactivation rapide, un rythme plus lent de d&eacute;composition actuelle et un d&eacute;placement d&eacute;polaris&eacute; dans la d&eacute;pendance de la tension de la disponibilit&eacute;. Cette &eacute;tude a identifi&eacute; une nouvelle mutation de PAM avec un ph&eacute;notype s&eacute;v&egrave;re et met l&#39;accent sur l&#39;importance de l&#39;extr&eacute;mit&eacute; C-terminale de l&#39;inactivation rapide du canal sodique. Nerf du muscle 39:666-673, 2009.

Nouvelle mutation du canal Na + dans la forme s&eacute;v&egrave;re de myotonie aggrav&eacute;e de potassium.

Myotonie manifestiert sich in mehreren erblichen Krankheiten, einschlie&szlig;lich hyperkali&auml;mische periodische Paralyse (HyperPP), Paramyotonia Congenita (PMC) und Kalium-versch&auml;rft Myotonie (PAM). Dies sind allelische Erkrankungen aus Missense-Mutationen des Gens, das die Skelettmuskulatur Natriumkanal, Nav1.4 codes. Dar&uuml;ber hinaus wurde eine schwere Form der PAM als Myotonia Permanens festgelegt. Eine neue Mutation des Nav1.4, Q1633E, wurde in einer japanischen Familie pr&auml;sentiert mit dem PAM-Ph&auml;notyp identifiziert. Der proband litt Zyanotisch Angriffe im Kleinkindalter. Der R&uuml;ckstand mutierte Aminos&auml;ure befindet sich auf der EF-Hand-Kalzium-Bindung-Motiv in der intrazellul&auml;ren C-Terminus. Eine funktionale Analyse des mutierten Kanal mit der Spannung-Clamp-Methode ergab Unterbrechung der schnelle Inaktivierung, langsamer des aktuellen Verfalls und depolarisiert Verlagerung in Abh&auml;ngigkeit von der Spannung der Verf&uuml;gbarkeit. Diese Studie hat eine neue Mutation des PAM mit einem schweren Ph&auml;notyp und betont die Bedeutung von der C-Terminus f&uuml;r schnelle Inaktivierung der Natrium-Kanal. Muskel-Nerv 39:666-673, 2009.

Neue Mutation der Na-Kanals in die schwere Form der Myotonie Kalium-versch&auml;rft.

Miotonia si manifesta in diverse malattie ereditarie, tra cui paralisi periodica ipokaliemica (HyperPP), la paramiotonia congenita (PMC) e miotonia aggravata dal potassio (PAM). Queste sono malattie alleliche provenienti da mutazioni missenso nel gene che codifica il canale del sodio muscolo scheletrico, Nav1.4. Inoltre, una grave forma di PAM &egrave; stata designata come forma di miotonia. Una nuova mutazione di Nav1.4, Q1633E, &egrave; stata identificata in una famiglia giapponese presentando con il fenotipo di PAM. Il probando sofferto attacchi cianotico durante l&#39;infanzia. I residui dell&#39;amminoacido mutato si trovano sul motivo calcio-associazione EF-mano nel C-terminale intracellulare. Un&#39;analisi funzionale del canale mutante utilizzando il metodo di tensione-morsetto rivelato interruzioni di inattivazione veloce, un tasso pi&ugrave; lento di decadimento attuale e uno spostamento depolarizzato nella dipendenza della tensione di disponibilit&agrave;. Questo studio ha identificato una nuova mutazione di PAM con un fenotipo grave e sottolinea l&#39;importanza del C-terminale per rapida inattivazione del canale del sodio. Muscolo nervo 39:666-673, 2009.

Nuova mutazione del canale Na nella forma grave di miotonia aggravata dal potassio.

&#x7B4B;&#x7DCA;&#x5F35;&#x306E;&#x5468;&#x671F;&#x6027;&#x56DB;&#x80A2;&#x9EBB;&#x75FA; (HyperPP)&#x3001;paramyotonia &#x5148;&#x5929;&#x6027; (PMC) &#x30AB;&#x30EA;&#x30A6;&#x30E0;&#x60AA;&#x5316;&#x7B4B;&#x7DCA;&#x5F35; (PAM) &#x306A;&#x3069;&#x3001;&#x3044;&#x304F;&#x3064;&#x304B;&#x306E;&#x907A;&#x4F1D;&#x6027;&#x75BE;&#x60A3;&#x306E;&#x30DE;&#x30CB;&#x30D5;&#x30A7;&#x30B9;&#x30C8;&#x3057;&#x307E;&#x3059;&#x3002;&#x3053;&#x308C;&#x3089;&#x306F; Nav1.4 &#x9AA8;&#x683C;&#x7B4B;&#x30CA;&#x30C8;&#x30EA;&#x30A6;&#x30E0; &#x30C1;&#x30E3;&#x30CD;&#x30EB; &#x30B3;&#x30FC;&#x30C9;&#x907A;&#x4F1D;&#x5B50;&#x306E;&#x30DF;&#x30B9;&#x30BB;&#x30F3;&#x30B9;&#x5909;&#x7570;&#x304B;&#x3089;&#x767A;&#x4FE1;&#x3055;&#x308C;&#x308B;&#x5BFE;&#x7ACB;&#x907A;&#x4F1D;&#x5B50;&#x306E;&#x75BE;&#x60A3;&#x3067;&#x3059;&#x3002;&#x307E;&#x305F;&#x3001;PAM &#x306E;&#x91CD;&#x75C7;&#x7B4B;&#x7DCA;&#x5F35; permanens &#x3068;&#x3057;&#x3066;&#x6307;&#x5B9A;&#x3055;&#x308C;&#x3066;&#x3044;&#x307E;&#x3059;&#x3002;Nav1.4&#x3001;Q1633E &#x306E;&#x65B0;&#x3057;&#x3044;&#x7A81;&#x7136;&#x5909;&#x7570;&#x3067;&#x63D0;&#x793A;&#x3055;&#x308C;&#x305F;&#x65E5;&#x672C;&#x4EBA;&#x5BB6;&#x65CF;&#x306B;&#x30D1;&#x30E0;&#x8868;&#x73FE;&#x578B;&#x3068;&#x540C;&#x5B9A;&#x3055;&#x308C;&#x307E;&#x3057;&#x305F;&#x3002;&#x767A;&#x7AEF;&#x8005;&#x30C1;&#x30A2;&#x30CE;&#x30FC;&#x30BC;&#x653B;&#x6483;&#x304B;&#x3089;&#x4E73;&#x5150;&#x671F;&#x306B;&#x82E6;&#x3057;&#x3093;&#x3060;&#x3002;&#x5909;&#x7570;&#x3059;&#x308B;&#x30A2;&#x30DF;&#x30CE;&#x9178;&#x6B8B;&#x57FA;&#x306F;&#x7D30;&#x80DE;&#x5185; C &#x672B;&#x7AEF;&#x306E; EF &#x30CF;&#x30F3;&#x30C9; &#x30AB;&#x30EB;&#x30B7;&#x30A6;&#x30E0;&#x7D50;&#x5408;&#x30E2;&#x30C1;&#x30FC;&#x30D5;&#x306B;&#x95A2;&#x3059;&#x308B;&#x3042;&#x308A;&#x307E;&#x3059;&#x3002;&#x96FB;&#x5727;&#x30AF;&#x30E9;&#x30F3;&#x30D7;&#x6CD5;&#x3092;&#x7528;&#x3044;&#x305F;&#x5909;&#x7570;&#x30C1;&#x30E3;&#x30CD;&#x30EB;&#x306E;&#x6A5F;&#x80FD;&#x89E3;&#x6790;&#x306E;&#x4E0D;&#x6D3B;&#x6027;&#x5316;&#x3092;&#x96FB;&#x6D41;&#x6E1B;&#x8870;&#x306E;&#x9045;&#x3044;&#x901F;&#x5EA6;&#x3001;&#x7121;&#x504F;&#x5149;&#x30B7;&#x30D5;&#x30C8;&#x4E2D;&#x65AD;&#x53EF;&#x7528;&#x6027;&#x306E;&#x96FB;&#x5727;&#x4F9D;&#x5B58;&#x6027;&#x3092;&#x660E;&#x3089;&#x304B;&#x306B;&#x3057;&#x307E;&#x3057;&#x305F;&#x3002;&#x672C;&#x7814;&#x7A76;&#x306F;&#x3001;PAM &#x306E;&#x65B0;&#x3057;&#x3044;&#x5909;&#x7570;&#x3092;&#x6709;&#x3059;&#x308B;&#x91CD;&#x5EA6;&#x306E;&#x8868;&#x73FE;&#x578B;&#x8B58;&#x5225;&#x3001;&#x30CA;&#x30C8;&#x30EA;&#x30A6;&#x30E0; &#x30C1;&#x30E3;&#x30F3;&#x30CD;&#x30EB;&#x306E;&#x4E0D;&#x6D3B;&#x6027;&#x5316;&#x306E;&#x305F;&#x3081;&#x306E; C &#x672B;&#x7AEF;&#x306E;&#x91CD;&#x8981;&#x6027;&#x3092;&#x5F37;&#x8ABF;&#x3057;&#x3066;&#x3044;&#x307E;&#x3059;&#x3002;&#x7B4B;&#x8089;&#x306E;&#x795E;&#x7D4C; 39:666-673&#x3001;2009&#x5E74;&#x3002;

&#x7B4B;&#x7DCA;&#x5F35;&#x306E;&#x30AB;&#x30EA;&#x30A6;&#x30E0;&#x60AA;&#x5316;&#x306E;&#x6DF1;&#x523B;&#x306A;&#x5F62;&#x3067;&#x306E; Na &#x30C1;&#x30E3;&#x30CD;&#x30EB;&#x306E;&#x65B0;&#x3057;&#x3044;&#x7A81;&#x7136;&#x5909;&#x7570;&#x3002;

Myotonia&#xB294; hyperkalemic &#xC8FC;&#xAE30; &#xC131; &#xB9C8;&#xBE44; (HyperPP), &#xCE7C;&#xB968; &#xC545;&#xD654; myotonia (PAM), paramyotonia congenita (PMC) &#xB4F1; &#xC5EC;&#xB7EC; &#xAC00;&#xC9C0; &#xC720;&#xC804; &#xC9C8;&#xD658;&#xC5D0;&#xC11C; &#xBA85;&#xC2DC; &#xD55C;&#xB2E4;. &#xC774;&#xB4E4;&#xC740; &#xC720;&#xC804;&#xC790; &#xC7A5;&#xC560; &#xACE8;&#xACA9; &#xADFC;&#xC721; &#xB098;&#xD2B8;&#xB968; &#xCC44;&#xB110; nav1.4&#xB97C; &#xCF54;&#xB4DC; &#xD558;&#xB294; &#xC720;&#xC804;&#xC790;&#xC758; &#xBCC0;&#xC774; missense&#xC5D0;&#xC11C; &#xBC1C;&#xC0DD; &#xD569;&#xB2C8;&#xB2E4;. &#xB610;&#xD55C;, &#xC2EC;&#xAC01;&#xD55C; &#xD615;&#xD0DC;&#xC758; &#xD338; myotonia permanens&#xB85C; &#xC9C0;&#xC815; &#xB418;&#xC5B4; &#xC788;&#xB2E4;. Nav1.4, Q1633E&#xC758; &#xC0C8;&#xB85C;&#xC6B4; &#xB3CC;&#xC5F0;&#xBCC0;&#xC774; &#xC77C;&#xBCF8; &#xAC00;&#xC871; &#xD338; phenotype&#xACFC; &#xC81C;&#xC2DC;&#xC5D0; &#xD655;&#xC778; &#xB418;&#xC5C8;&#xB2E4;. Proband&#xC5D0;&#xC11C; &#xACE0;&#xD1B5;&#xC744; &#xCCAD;&#xC0C9; &#xACF5;&#xACA9; &#xCD08;&#xAE30; &#xB2E8;&#xACC4; &#xB3D9;&#xC548;. &#xB3CC;&#xC5F0;&#xBCC0;&#xC774; &#xC544;&#xBBF8;&#xB178;&#xC0B0; &#xC794;&#xB958;&#xBB3C; EF &#xC190;&#xC744; &#xCE7C;&#xC298; &#xBC14;&#xC778;&#xB529; &#xBAA8;&#xD2F0;&#xBE0C; &#xC138;&#xD3EC;&#xB0B4; C-&#xB9D0;&#xB2E8;&#xC5D0; &#xC704;&#xCE58; &#xD558; &#xACE0; &#xC788;&#xC2B5;&#xB2C8;&#xB2E4;. &#xC804;&#xC555; &#xD074;&#xB7A8;&#xD504; &#xBA54;&#xC11C;&#xB4DC;&#xB97C; &#xC0AC;&#xC6A9; &#xD558; &#xC5EC; &#xB3CC;&#xC5F0;&#xBCC0;&#xC774; &#xCC44;&#xB110;&#xC758; &#xAE30;&#xB2A5; &#xBD84;&#xC11D; &#xC5EC;&#xBD80;&#xC758; &#xC804;&#xC555; &#xC758;&#xC874;&#xC131;&#xC5D0; &#xBE60;&#xB978; &#xBE44;&#xD65C;&#xC131;&#xD654;, &#xD604;&#xC7AC; &#xCDA9;&#xC758; &#xB290;&#xB9B0; &#xC18D;&#xB3C4; depolarized shift&#xC758; &#xC911;&#xB2E8;&#xC744; &#xBC1D;&#xD614;&#xB2E4;. &#xC774; &#xC5F0;&#xAD6C;&#xB294; &#xC2EC;&#xAC01;&#xD55C; &#xD45C;&#xD604; &#xD615;&#xC73C;&#xB85C; &#xD338;&#xC758; &#xC0C8;&#xB85C;&#xC6B4; &#xBCC0;&#xC774; &#xBC1C;&#xACAC; &#xD588;&#xB2E4; &#xACE0; &#xB098;&#xD2B8;&#xB968; &#xCC44;&#xB110;&#xC758; &#xBE60;&#xB978; &#xBE44;&#xD65C;&#xC131;&#xD654;&#xC5D0; &#xB300; &#xD55C; C-&#xB9D0;&#xB2E8;&#xC758; &#xC911;&#xC694;&#xC131;&#xC744; &#xAC15;&#xC870;. &#xADFC;&#xC721; &#xC2E0;&#xACBD; 39: 666-673, 2009.

&#xCE7C;&#xB968; &#xC545;&#xD654; myotonia&#xC758; &#xC2EC;&#xD55C; &#xD615;&#xD0DC;&#xB85C; &#xB098; &#xCC44;&#xB110;&#xC758; &#xC0C8;&#xB85C;&#xC6B4; &#xB3CC;&#xC5F0;&#xBCC0;&#xC774;.

Mioton&iacute;a se manifiesta en varias enfermedades hereditarias, incluyendo par&aacute;lisis peri&oacute;dica hipercali&eacute;mica (HyperPP), paramioton&iacute;a cong&eacute;nita (PMC) y potasio-agravado mioton&iacute;a (PAM). Se trata de trastornos al&eacute;licos origina mutaciones sin sentido en el gen que codifica el canal de sodio del m&uacute;sculo esquel&eacute;tico, Nav1.4. Por otra parte, una forma severa de PAM ha sido designada como mioton&iacute;a permanens. Una nueva mutaci&oacute;n de Nav1.4, Q1633E, fue identificada en una familia japonesa que presenta con el fenotipo de PAM. El proband sufr&iacute;a ataques cian&oacute;ticos durante la infancia. El residuo de amino&aacute;cido mutado se encuentra en el motivo de uni&oacute;n a calcio EF-mano en el c-terminal intracelular. Un an&aacute;lisis funcional del mutante canal utilizando el m&eacute;todo de tensi&oacute;n-abrazadera revel&oacute; perturbaci&oacute;n de inactivaci&oacute;n r&aacute;pida, una velocidad m&aacute;s lenta decadencia actual y un cambio despolarizado en la dependencia de voltaje de la disponibilidad. Este estudio ha identificado una nueva mutaci&oacute;n del PAM con un fenotipo severo y subraya la importancia de la c-terminal de r&aacute;pida inactivaci&oacute;n del canal del sodio. Nervio del m&uacute;sculo 39:666-673, 2009.

Nueva mutaci&oacute;n del canal Na en la forma severa de mioton&iacute;a agravada de potasio.

Myotonic dystrophy type 1 (DM1) is an RNA gain-of-function disorder in which abnormally expanded CTG repeats of DMPK sequestrate a splicing trans-factor MBNL1 and upregulate another splicing trans-factor CUGBP1. To identify a diverse array of aberrantly spliced genes, we performed the exon array analysis of DM1 muscles. We analyzed 72 exons by RT-PCR and found that 27 were aberrantly spliced, whereas 45 were not. Among these, 25 were novel and especially splicing aberrations of LDB3 exon 4 and TTN exon 45 were unique to DM1. Retrospective analysis revealed that four parameters efficiently detect aberrantly spliced exons: (i) the signal intensity is high; (ii) the ratio of probe sets with reliable signal intensities (that is, detection above background P-value=0.000) is high within a gene; (iii) the splice index (SI) is high; and (iv) SI is deviated from SIs of the other exons that can be estimated by calculating the deviation value (DV). Application of the four parameters gave rise to a sensitivity of 77.8% and a specificity of 95.6% in our data set. We propose that calculation of DV, which is unique to our analysis, is of particular importance in analyzing the exon array data.

Four parameters increase the sensitivity and specificity of the exon array analysis and disclose 25 novel aberrantly spliced exons in myotonic dystrophy.

Water intoxication is a life-threatening disorder accompanied by brain function impairment due to severe dilutional hyponatremia. We treated a 22-year-old man without psychotic illness who had been put in a detention facility. He drank 6 liters of water over a 3-hour period at the facility as a game's penalty, and he showed progressive psychiatric and neurological signs including restlessness, peculiar behavior and convulsions. On his admission, 15 h after the discontinuation of the water drinking, he was in a coma, showing intermittent convulsions and remarkable hyponatremia (120 mmol/l). Because his laboratory tests showed hypertonic urine and normal sodium excretion, the diagnosis of secondary development of syndrome of inappropriate secretion of antidiuretic hormone (SIADH) was strongly suggested and later confirmed by the suppression of the renin-aldosterone system and the inappropriately elevated secretion of ADH. Saline infusion and an initial administration of furosemide in addition to dexamethasone as treatments for the patient's brain edema successfully improved his laboratory data and clinical signs by the 3rd hospital day, and he was returned to the facility without physical or psychiatric abnormalities on the 6th day. The secondary SIADH might have been due to the prolonged emesis, recurrent convulsions and rapid elevation of intracranial pressure.

A case of water intoxication with prolonged hyponatremia caused by excessive water drinking and secondary SIADH.

Myotonic dystrophy type 1 (DM1) is caused by transcription of CUG repeat RNA, which causes sequestration of muscleblind-like 1 (MBNL1) and upregulation of CUG triplet repeat RNA-binding protein (CUG-BP1). In DM1, dysregulation of these proteins contributes to many aberrant splicing events, causing various symptoms of the disorder. Here, we demonstrate the occurrence of aberrant splicing of LIM domain binding 3 (LDB3) exon 11 in DM1 skeletal muscle. Exon array surveys, RT-PCR, and western blotting studies demonstrated that exon 11 inclusion was DM1 specific and could be reproduced by transfection of a minigene containing the CTG repeat expansion. Moreover, we found that the LDB3 exon 11-positive isoform had reduced affinity for PKC compared to the exon 11-negative isoform. Since PKC exhibits hyperactivation in DM1 and stabilizes CUG-BP1 by phosphorylation, aberrant splicing of LDB3 may contribute to CUG-BP1 upregulation through changes in its affinity for PKC.

LDB3 splicing abnormalities are specific to skeletal muscles of patients with myotonic dystrophy type 1 and alter its PKC binding affinity.

An enlarged tongue (macroglossia) has been reported in advanced-stage patients with amyotrophic lateral sclerosis (ALS).

Macroglossia in advanced amyotrophic lateral sclerosis.

Myotonic dystrophy type 1 (DM1) is caused by abnormal expansion of CTG repeats in the 3' untranslated region of the DMPK gene. Expanded CTG repeats are transcribed into RNA and make an aggregate with a splicing regulator, MBNL1, in the nucleus, which is called the nuclear foci. The nuclear foci sequestrates and downregulates availability of MBNL1. Symptomatic treatments are available for DM1, but no rational therapy is available. In this study, we found that a nonsteroidal anti-inflammatory drug (NSAID), phenylbutazone (PBZ), upregulated the expression of MBNL1 in C2C12 myoblasts as well as in the HSA(LR) mouse model for DM1. In the DM1 mice model, PBZ ameliorated aberrant splicing of Clcn1, Nfix, and Rpn2. PBZ increased expression of skeletal muscle chloride channel, decreased abnormal central nuclei of muscle fibers, and improved wheel-running activity in HSA(LR) mice. We found that the effect of PBZ was conferred by two distinct mechanisms. First, PBZ suppressed methylation of an enhancer region in Mbnl1 intron 1, and enhanced transcription of Mbnl1 mRNA. Second, PBZ attenuated binding of MBNL1 to abnormally expanded CUG repeats in cellulo and in vitro. Our studies suggest that PBZ is a potent therapeutic agent for DM1 that upregulates availability of MBNL1.

Phenylbutazone induces expression of MBNL1 and suppresses formation of MBNL1-CUG RNA foci in a mouse model of myotonic dystrophy.

Patients with amyotrophic lateral sclerosis (ALS) often suffer from salivation problems such as drooling and dry mouth. We examined resting salivation rate cross-sectionally in 66 advanced ALS patients with tracheostomy invasive ventilation using a cotton roll method, and investigated clinical factors associated with salivation rate. Resting salivation rate in the patients was well preserved (median value 0.6 g/min), and was significantly more increased in patients with impairment of jaw movement (P = 0.007) or mouth opening (P = 0.003) than in patients with less impairment, and in patients with the mouth being constantly open ≥ 10 mm in rostrocaudal length than in patients with < 10 mm. These data indicate that salivation rate was increased with progression of dysfunction of voluntary jaw movement. Appropriate oral care is required in advanced ALS patients to maintain their oral hygiene and to avoid penetration of saliva into the airway.

Article	Year
A patient with myotonic dystrophy type 1 (DM 1) accompanied by laryngeal and renal cell carcinomas had a small CTG triplet repeat expansion but no somatic instability in normal tissues. Internal medicine (Tokyo, Japan)\| PubMed ID: 11993794	2002
Thr1313Met mutation in skeletal muscle sodium channels in a Japanese family with paramyotonia congenita. Internal medicine (Tokyo, Japan)\| PubMed ID: 14518676	2003
[Severe hypocalcemia compatible with idiopathic hypoparathyroidism associated with psoriasis vulgaris]. Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine\| PubMed ID: 14743761	2003
Eye movement disorders in myotonic dystrophy type 1. Acta oto-laryngologica. Supplementum\| PubMed ID: 18340575	2007
New mutation of the Na channel in the severe form of potassium-aggravated myotonia. Muscle & nerve\| PubMed ID: 19347921	2009
Four parameters increase the sensitivity and specificity of the exon array analysis and disclose 25 novel aberrantly spliced exons in myotonic dystrophy. Journal of human genetics\| PubMed ID: 22513715	2012
A case of water intoxication with prolonged hyponatremia caused by excessive water drinking and secondary SIADH. Case reports in nephrology and urology\| PubMed ID: 24570685	2013
LDB3 splicing abnormalities are specific to skeletal muscles of patients with myotonic dystrophy type 1 and alter its PKC binding affinity. Neurobiology of disease\| PubMed ID: 24878509	2014
Macroglossia in advanced amyotrophic lateral sclerosis. Muscle & nerve\| PubMed ID: 26816340	2016
Phenylbutazone induces expression of MBNL1 and suppresses formation of MBNL1-CUG RNA foci in a mouse model of myotonic dystrophy. Scientific reports\| PubMed ID: 27126921	2016
Analysis of resting salivation rate in patients with amyotrophic lateral sclerosis using tracheostomy invasive ventilation. Rinsho shinkeigaku = Clinical neurology\| PubMed ID: 27356730	2016

Masanobu Kinoshita

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