RBCC

Full text data of SLC2A1

SLC2A1 (GLUT1) [Confidence: high (present in two of the MS resources)]
Solute carrier family 2, facilitated glucose transporter member 1 (Glucose transporter type 1, erythrocyte/brain; GLUT-1; HepG2 glucose transporter)

hRBCD IPI00220194
IPI00220194 Solute carrier family 2, facilitated glucose transporter, member 1 Solute carrier family 2, facilitated glucose transporter, member 1 membrane n/a 17 3 28 29 28 26 26 72 11 29 16 n/a 1 6 6 1 12 11 11 integral membrane protein TFDEIASGFR, TPEELFHPLGADSQV, LRGTADVTHDLQEMK, KVTILELFRSP found at its expected molecular weight found at molecular weight

UniProt P11166
ID GTR1_HUMAN Reviewed; 492 AA.
AC P11166; A8K9S6; B2R620; D3DPX0; O75535; Q147X2;
DT 01-JUL-1989, integrated into UniProtKB/Swiss-Prot.
read moreDT 03-OCT-2006, sequence version 2.
DT 22-JAN-2014, entry version 171.
DE RecName: Full=Solute carrier family 2, facilitated glucose transporter member 1;
DE AltName: Full=Glucose transporter type 1, erythrocyte/brain;
DE Short=GLUT-1;
DE AltName: Full=HepG2 glucose transporter;
GN Name=SLC2A1; Synonyms=GLUT1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], PARTIAL PROTEIN SEQUENCE, GLYCOSYLATION AT
RP ASN-45, LACK OF GLYCOSYLATION AT ASN-411, AND MASS SPECTROMETRY.
RX PubMed=3839598; DOI=10.1126/science.3839598;
RA Mueckler M., Caruso C., Baldwin S.A., Panico M., Blench I.,
RA Morris H.R., Allard W.J., Lienhard G.E., Lodish H.F.;
RT "Sequence and structure of a human glucose transporter.";
RL Science 229:941-945(1985).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain, and Trachea;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-6.
RX PubMed=2834252; DOI=10.2337/diab.37.5.657;
RA Fukumoto H., Seino S., Imura H., Seino Y., Bell G.I.;
RT "Characterization and expression of human HepG2/erythrocyte glucose-
RT transporter gene.";
RL Diabetes 37:657-661(1988).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 150-492.
RC TISSUE=Brain;
RA Yu W., Gibbs R.A.;
RL Submitted (JUN-1998) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 294-423.
RC TISSUE=Articular cartilage;
RA Neama G., Richardson S., Bell S., Carter S., Mobasheri A.;
RT "Molecular characterization and cloning of glucose transporters in
RT human articular chondrocytes.";
RL Submitted (MAY-2001) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP SUBCELLULAR LOCATION [LARGE SCALE ANALYSIS], AND MASS SPECTROMETRY.
RC TISSUE=Melanoma;
RX PubMed=17081065; DOI=10.1021/pr060363j;
RA Chi A., Valencia J.C., Hu Z.-Z., Watabe H., Yamaguchi H.,
RA Mangini N.J., Huang H., Canfield V.A., Cheng K.C., Yang F., Abe R.,
RA Yamagishi S., Shabanowitz J., Hearing V.J., Wu C., Appella E.,
RA Hunt D.F.;
RT "Proteomic and bioinformatic characterization of the biogenesis and
RT function of melanosomes.";
RL J. Proteome Res. 5:3135-3144(2006).
RN [9]
RP IDENTIFICATION IN A COMPLEX WITH ADD2 AND DMTN, INTERACTION WITH DMTN,
RP AND IDENTIFICATION BY MASS SPECTROMETRY.
RX PubMed=18347014; DOI=10.1074/jbc.M707818200;
RA Khan A.A., Hanada T., Mohseni M., Jeong J.J., Zeng L., Gaetani M.,
RA Li D., Reed B.C., Speicher D.W., Chishti A.H.;
RT "Dematin and adducin provide a novel link between the spectrin
RT cytoskeleton and human erythrocyte membrane by directly interacting
RT with glucose transporter-1.";
RL J. Biol. Chem. 283:14600-14609(2008).
RN [10]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of
RT the kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [11]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-45, AND MASS SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19349973; DOI=10.1038/nbt.1532;
RA Wollscheid B., Bausch-Fluck D., Henderson C., O'Brien R., Bibel M.,
RA Schiess R., Aebersold R., Watts J.D.;
RT "Mass-spectrometric identification and relative quantification of N-
RT linked cell surface glycoproteins.";
RL Nat. Biotechnol. 27:378-386(2009).
RN [12]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-478, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [13]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [14]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-490, AND MASS
RP SPECTROMETRY.
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [15]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND MASS SPECTROMETRY.
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E.,
RA Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
RA Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-
RT terminal acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [16]
RP INTERACTION WITH SNX27.
RX PubMed=23563491; DOI=10.1038/ncb2721;
RA Steinberg F., Gallon M., Winfield M., Thomas E.C., Bell A.J.,
RA Heesom K.J., Tavare J.M., Cullen P.J.;
RT "A global analysis of SNX27-retromer assembly and cargo specificity
RT reveals a function in glucose and metal ion transport.";
RL Nat. Cell Biol. 15:461-471(2013).
RN [17]
RP VARIANT GLUT1DS1 ILE-310.
RX PubMed=10227690; DOI=10.1023/A:1022544131826;
RA Klepper J., Wang D., Fischbarg J., Vera J.C., Jarjour I.T.,
RA O'Driscoll K.R., De Vivo D.C.;
RT "Defective glucose transport across brain tissue barriers: a newly
RT recognized neurological syndrome.";
RL Neurochem. Res. 24:587-594(1999).
RN [18]
RP VARIANTS GLUT1DS1 PHE-66; LEU-126; LYS-146; GLU-256 AND TRP-333.
RX PubMed=10980529;
RX DOI=10.1002/1098-1004(200009)16:3<224::AID-HUMU5>3.3.CO;2-G;
RA Wang D., Kranz-Eble P., De Vivo D.C.;
RT "Mutational analysis of GLUT1 (SLC2A1) in Glut-1 deficiency
RT syndrome.";
RL Hum. Mutat. 16:224-231(2000).
RN [19]
RP ERRATUM.
RA Wang D., Kranz-Eble P., De Vivo D.C.;
RL Hum. Mutat. 16:527-527(2000).
RN [20]
RP VARIANT GLUT1DS1 HIS-126.
RX PubMed=11603379; DOI=10.1002/ana.1222;
RA Brockmann K., Wang D., Korenke C.G., von Moers A., Ho Y.-Y.,
RA Pascual J.M., Kuang K., Yang H., Ma L., Kranz-Eble P., Fischbarg J.,
RA Hanefeld F., De Vivo D.C.;
RT "Autosomal dominant Glut-1 deficiency syndrome and familial
RT epilepsy.";
RL Ann. Neurol. 50:476-485(2001).
RN [21]
RP VARIANT GLUT1DS1 ASP-91.
RX PubMed=11136715; DOI=10.1093/hmg/10.1.63;
RA Klepper J., Willemsen M., Verrips A., Guertsen E., Herrmann R.,
RA Kutzick C., Floercken A., Voit T.;
RT "Autosomal dominant transmission of GLUT1 deficiency.";
RL Hum. Mol. Genet. 10:63-68(2001).
RN [22]
RP VARIANTS GLUT1DS1 CYS-126; HIS-126; LYS-146; CYS-153 AND TRP-333.
RX PubMed=12325075; DOI=10.1002/ana.10311;
RA Pascual J.M., van Heertum R.L., Wang D., Engelstad K., De Vivo D.C.;
RT "Imaging the metabolic footprint of Glut1 deficiency on the brain.";
RL Ann. Neurol. 52:458-464(2002).
RN [23]
RP VARIANT GLUT1DS2 ILE-34.
RX PubMed=14605501; DOI=10.1023/A:1025999914822;
RA Overweg-Plandsoen W.C.G., Groener J.E.M., Wang D., Onkenhout W.,
RA Brouwer O.F., Bakker H.D., De Vivo D.C.;
RT "GLUT-1 deficiency without epilepsy -- an exceptional case.";
RL J. Inherit. Metab. Dis. 26:559-563(2003).
RN [24]
RP VARIANTS GLUT1DS1 SER-34; HIS-126; SER-130; CYS-153; LEU-169 DEL;
RP MET-295 AND TRP-333, AND CHARACTERIZATION OF VARIANTS GLUT1 DEFICIENCY
RP SER-34; HIS-126; SER-130; CYS-153; LEU-169 DEL; MET-295 AND TRP-333.
RX PubMed=15622525; DOI=10.1002/ana.20331;
RA Wang D., Pascual J.M., Yang H., Engelstad K., Jhung S., Sun R.P.,
RA De Vivo D.C.;
RT "Glut-1 deficiency syndrome: clinical, genetic, and therapeutic
RT aspects.";
RL Ann. Neurol. 57:111-118(2005).
RN [25]
RP VARIANTS GLUT1DS2 THR-275; 282-GLN--SER-285 DEL AND SER-314.
RX PubMed=18451999; DOI=10.1172/JCI34438;
RA Weber Y.G., Storch A., Wuttke T.V., Brockmann K., Kempfle J.,
RA Maljevic S., Margari L., Kamm C., Schneider S.A., Huber S.M.,
RA Pekrun A., Roebling R., Seebohm G., Koka S., Lang C., Kraft E.,
RA Blazevic D., Salvo-Vargas A., Fauler M., Mottaghy F.M., Muenchau A.,
RA Edwards M.J., Presicci A., Margari F., Gasser T., Lang F.,
RA Bhatia K.P., Lehmann-Horn F., Lerche H.;
RT "GLUT1 mutations are a cause of paroxysmal exertion-induced
RT dyskinesias and induce hemolytic anemia by a cation leak.";
RL J. Clin. Invest. 118:2157-2168(2008).
RN [26]
RP VARIANT EIG12 PRO-223, VARIANTS GLUT1DS2 CYS-126 AND LEU-324,
RP CHARACTERIZATION OF VARIANT EIG12 PRO-223, AND CHARACTERIZATION OF
RP VARIANTS GLUT1DS2 CYS-126 AND LEU-324.
RX PubMed=19798636; DOI=10.1002/ana.21724;
RA Suls A., Mullen S.A., Weber Y.G., Verhaert K., Ceulemans B.,
RA Guerrini R., Wuttke T.V., Salvo-Vargas A., Deprez L., Claes L.R.,
RA Jordanova A., Berkovic S.F., Lerche H., De Jonghe P., Scheffer I.E.;
RT "Early-onset absence epilepsy caused by mutations in the glucose
RT transporter GLUT1.";
RL Ann. Neurol. 66:415-419(2009).
RN [27]
RP VARIANT GLUT1DS1 TYR-292 INS.
RX PubMed=19901175; DOI=10.1001/archneurol.2009.236;
RA Perez-Duenas B., Prior C., Ma Q., Fernandez-Alvarez E., Setoain X.,
RA Artuch R., Pascual J.M.;
RT "Childhood chorea with cerebral hypotrophy: a treatable GLUT1 energy
RT failure syndrome.";
RL Arch. Neurol. 66:1410-1414(2009).
RN [28]
RP VARIANTS GLUT1DS2 TRP-92 AND GLN-333.
RX PubMed=19630075; DOI=10.1002/mds.22507;
RA Schneider S.A., Paisan-Ruiz C., Garcia-Gorostiaga I., Quinn N.P.,
RA Weber Y.G., Lerche H., Hardy J., Bhatia K.P.;
RT "GLUT1 gene mutations cause sporadic paroxysmal exercise-induced
RT dyskinesias.";
RL Mov. Disord. 24:1684-1688(2009).
RN [29]
RP VARIANT GLUT1DS1 TRP-468.
RX PubMed=20221955; DOI=10.1055/s-0030-1248264;
RA Klepper J., Scheffer H., Elsaid M.F., Kamsteeg E.J., Leferink M.,
RA Ben-Omran T.;
RT "Autosomal recessive inheritance of GLUT1 deficiency syndrome.";
RL Neuropediatrics 40:207-210(2009).
RN [30]
RP VARIANTS GLUT1DS1 TYR-34; VAL-96; SER-130; VAL-155; CYS-212; HIS-212;
RP TRP-223; MET-295; GLN-329; GLN-333; ASP-382; ASP-405 AND LEU-485,
RP VARIANTS GLUT1DS2 TRP-93 AND HIS-153, AND VARIANT LEU-303.
RX PubMed=20129935; DOI=10.1093/brain/awp336;
RA Leen W.G., Klepper J., Verbeek M.M., Leferink M., Hofste T.,
RA van Engelen B.G., Wevers R.A., Arthur T., Bahi-Buisson N.,
RA Ballhausen D., Bekhof J., van Bogaert P., Carrilho I., Chabrol B.,
RA Champion M.P., Coldwell J., Clayton P., Donner E., Evangeliou A.,
RA Ebinger F., Farrell K., Forsyth R.J., de Goede C.G., Gross S.,
RA Grunewald S., Holthausen H., Jayawant S., Lachlan K., Laugel V.,
RA Leppig K., Lim M.J., Mancini G., Marina A.D., Martorell L.,
RA McMenamin J., Meuwissen M.E., Mundy H., Nilsson N.O., Panzer A.,
RA Poll-The B.T., Rauscher C., Rouselle C.M., Sandvig I., Scheffner T.,
RA Sheridan E., Simpson N., Sykora P., Tomlinson R., Trounce J., Webb D.,
RA Weschke B., Scheffer H., Willemsen M.A.;
RT "Glucose transporter-1 deficiency syndrome: the expanding clinical and
RT genetic spectrum of a treatable disorder.";
RL Brain 133:655-670(2010).
RN [31]
RP VARIANT GLUT1DS2 THR-317.
RX PubMed=21204808; DOI=10.1111/j.1528-1167.2010.02726.x;
RA Afawi Z., Suls A., Ekstein D., Kivity S., Neufeld M.Y., Oliver K.,
RA De Jonghe P., Korczyn A.D., Berkovic S.F.;
RT "Mild adolescent/adult onset epilepsy and paroxysmal exercise-induced
RT dyskinesia due to GLUT1 deficiency.";
RL Epilepsia 51:2466-2469(2010).
RN [32]
RP VARIANT GLUT1DS2 ILE-165.
RX PubMed=20621801; DOI=10.1016/j.jns.2010.05.017;
RA Urbizu A., Cuenca-Leon E., Raspall-Chaure M., Gratacos M., Conill J.,
RA Redecillas S., Roig-Quilis M., Macaya A.;
RT "Paroxysmal exercise-induced dyskinesia, writer's cramp, migraine with
RT aura and absence epilepsy in twin brothers with a novel SLC2A1
RT missense mutation.";
RL J. Neurol. Sci. 295:110-113(2010).
RN [33]
RP VARIANTS GLUT1DS2 ILE-95; PRO-223; SER-314 AND LEU-324, AND VARIANTS
RP GLUT1DS1 ASP-91 AND HIS-126.
RX PubMed=20574033; DOI=10.1212/WNL.0b013e3181eb58b4;
RA Mullen S.A., Suls A., De Jonghe P., Berkovic S.F., Scheffer I.E.;
RT "Absence epilepsies with widely variable onset are a key feature of
RT familial GLUT1 deficiency.";
RL Neurology 75:432-440(2010).
RN [34]
RP VARIANT GLUT1DS2 PRO-294.
RX PubMed=20830593; DOI=10.1007/s00415-010-5702-5;
RA Anheim M., Maillart E., Vuillaumier-Barrot S., Flamand-Rouviere C.,
RA Pineau F., Ewenczyk C., Riant F., Apartis E., Roze E.;
RT "Excellent response to acetazolamide in a case of paroxysmal
RT dyskinesias due to GLUT1-deficiency.";
RL J. Neurol. 258:316-317(2011).
RN [35]
RP VARIANTS DYT9 CYS-126 AND CYS-212.
RX PubMed=21832227; DOI=10.1212/WNL.0b013e31822e0479;
RA Weber Y.G., Kamm C., Suls A., Kempfle J., Kotschet K., Schule R.,
RA Wuttke T.V., Maljevic S., Liebrich J., Gasser T., Ludolph A.C.,
RA Van Paesschen W., Schols L., De Jonghe P., Auburger G., Lerche H.;
RT "Paroxysmal choreoathetosis/spasticity (DYT9) is caused by a GLUT1
RT defect.";
RL Neurology 77:959-964(2011).
RN [36]
RP VARIANT EIG12 CYS-232, AND CHARACTERIZATION OF VARIANT EIG12 CYS-232.
RX PubMed=22282645; DOI=10.1212/WNL.0b013e318247ff54;
RA Striano P., Weber Y.G., Toliat M.R., Schubert J., Leu C., Chaimana R.,
RA Baulac S., Guerrero R., LeGuern E., Lehesjoki A.E., Polvi A.,
RA Robbiano A., Serratosa J.M., Guerrini R., Nurnberg P., Sander T.,
RA Zara F., Lerche H., Marini C.;
RT "GLUT1 mutations are a rare cause of familial idiopathic generalized
RT epilepsy.";
RL Neurology 78:557-562(2012).
CC -!- FUNCTION: Facilitative glucose transporter. This isoform may be
CC responsible for constitutive or basal glucose uptake. Has a very
CC broad substrate specificity; can transport a wide range of aldoses
CC including both pentoses and hexoses.
CC -!- SUBUNIT: Interacts with GIPC (via PDZ domain) (By similarity).
CC Found in a complex with ADD2, DMTN and SLC2A1. Interacts (via C-
CC terminus cytoplasmic region) with DMTN isoform 2. Interacts with
CC SNX27; the interaction is required when endocytosed to prevent
CC degradation in lysosomes and promote recycling to the plasma
CC membrane.
CC -!- INTERACTION:
CC Self; NbExp=3; IntAct=EBI-717153, EBI-717153;
CC -!- SUBCELLULAR LOCATION: Cell membrane; Multi-pass membrane protein
CC (By similarity). Melanosome. Note=Localizes primarily at the cell
CC surface (By similarity). Identified by mass spectrometry in
CC melanosome fractions from stage I to stage IV.
CC -!- TISSUE SPECIFICITY: Expressed at variable levels in many human
CC tissues.
CC -!- DISEASE: GLUT1 deficiency syndrome 1 (GLUT1DS1) [MIM:606777]: A
CC neurologic disorder showing wide phenotypic variability. The most
CC severe 'classic' phenotype comprises infantile-onset epileptic
CC encephalopathy associated with delayed development, acquired
CC microcephaly, motor incoordination, and spasticity. Onset of
CC seizures, usually characterized by apneic episodes, staring
CC spells, and episodic eye movements, occurs within the first 4
CC months of life. Other paroxysmal findings include intermittent
CC ataxia, confusion, lethargy, sleep disturbance, and headache.
CC Varying degrees of cognitive impairment can occur, ranging from
CC learning disabilities to severe mental retardation. Note=The
CC disease is caused by mutations affecting the gene represented in
CC this entry.
CC -!- DISEASE: GLUT1 deficiency syndrome 2 (GLUT1DS2) [MIM:612126]: A
CC clinically variable disorder characterized primarily by onset in
CC childhood of paroxysmal exercise-induced dyskinesia. The
CC dyskinesia involves transient abnormal involuntary movements, such
CC as dystonia and choreoathetosis, induced by exercise or exertion,
CC and affecting the exercised limbs. Some patients may also have
CC epilepsy, most commonly childhood absence epilepsy. Mild mental
CC retardation may also occur. In some patients involuntary exertion-
CC induced dystonic, choreoathetotic, and ballistic movements may be
CC associated with macrocytic hemolytic anemia. Note=The disease is
CC caused by mutations affecting the gene represented in this entry.
CC -!- DISEASE: Epilepsy, idiopathic generalized 12 (EIG12) [MIM:614847]:
CC A disorder characterized by recurring generalized seizures in the
CC absence of detectable brain lesions and/or metabolic
CC abnormalities. Generalized seizures arise diffusely and
CC simultaneously from both hemispheres of the brain. Seizure types
CC include juvenile myoclonic seizures, absence seizures, and
CC generalized tonic-clonic seizures. In some EIG12 patients seizures
CC may remit with age. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- DISEASE: Dystonia 9 (DYT9) [MIM:601042]: An autosomal dominant
CC neurologic disorder characterized by childhood onset of paroxysmal
CC choreoathetosis and progressive spastic paraplegia. Most patients
CC show some degree of cognitive impairment. Other variable features
CC may include seizures, migraine headaches, and ataxia. Note=The
CC disease is caused by mutations affecting the gene represented in
CC this entry.
CC -!- SIMILARITY: Belongs to the major facilitator superfamily. Sugar
CC transporter (TC 2.A.1.1) family. Glucose transporter subfamily.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/SLC2A1";
CC -!- WEB RESOURCE: Name=Wikipedia; Note=GLUT1 entry;
CC URL="http://en.wikipedia.org/wiki/GLUT1";
CC -----------------------------------------------------------------------
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DR EMBL; K03195; AAA52571.1; -; mRNA.
DR EMBL; AK292791; BAF85480.1; -; mRNA.
DR EMBL; AK312403; BAG35317.1; -; mRNA.
DR EMBL; CH471059; EAX07124.1; -; Genomic_DNA.
DR EMBL; BC118590; AAI18591.1; -; mRNA.
DR EMBL; M20653; AAB61084.1; -; Genomic_DNA.
DR EMBL; AF070544; AAC28635.1; -; mRNA.
DR EMBL; AY034633; AAK56795.1; -; mRNA.
DR PIR; A27217; A27217.
DR RefSeq; NP_006507.2; NM_006516.2.
DR UniGene; Hs.473721; -.
DR PDB; 1SUK; Model; -; A=1-492.
DR PDBsum; 1SUK; -.
DR ProteinModelPortal; P11166; -.
DR SMR; P11166; 19-465.
DR DIP; DIP-23N; -.
DR IntAct; P11166; 5.
DR MINT; MINT-1386229; -.
DR STRING; 9606.ENSP00000416293; -.
DR BindingDB; P11166; -.
DR ChEMBL; CHEMBL2535; -.
DR DrugBank; DB00292; Etomidate.
DR GuidetoPHARMACOLOGY; 875; -.
DR TCDB; 2.A.1.1.28; the major facilitator superfamily (mfs).
DR PhosphoSite; P11166; -.
DR UniCarbKB; P11166; -.
DR DMDM; 115502394; -.
DR PaxDb; P11166; -.
DR PeptideAtlas; P11166; -.
DR PRIDE; P11166; -.
DR Ensembl; ENST00000426263; ENSP00000416293; ENSG00000117394.
DR GeneID; 6513; -.
DR KEGG; hsa:6513; -.
DR UCSC; uc001cik.2; human.
DR CTD; 6513; -.
DR GeneCards; GC01M043391; -.
DR HGNC; HGNC:11005; SLC2A1.
DR HPA; CAB002759; -.
DR MIM; 138140; gene.
DR MIM; 601042; phenotype.
DR MIM; 606777; phenotype.
DR MIM; 612126; phenotype.
DR MIM; 614847; phenotype.
DR neXtProt; NX_P11166; -.
DR Orphanet; 64280; Childhood absence epilepsy.
DR Orphanet; 71277; Encephalopathy due to GLUT1 deficiency.
DR Orphanet; 1942; Epilepsy with myoclonic-astatic seizures.
DR Orphanet; 168577; Hereditary cryohydrocytosis with reduced stomatin.
DR Orphanet; 53583; Paroxysmal dystonic choreathetosis with episodic ataxia and spasticity.
DR Orphanet; 98811; Paroxysmal exertion-induced dyskinesia.
DR PharmGKB; PA35875; -.
DR eggNOG; COG0477; -.
DR HOVERGEN; HBG014816; -.
DR KO; K07299; -.
DR OMA; LQCIVLP; -.
DR PhylomeDB; P11166; -.
DR Reactome; REACT_111217; Metabolism.
DR Reactome; REACT_116125; Disease.
DR Reactome; REACT_15518; Transmembrane transport of small molecules.
DR ChiTaRS; SLC2A1; human.
DR GeneWiki; GLUT1; -.
DR GenomeRNAi; 6513; -.
DR NextBio; 25327; -.
DR PRO; PR:P11166; -.
DR ArrayExpress; P11166; -.
DR Bgee; P11166; -.
DR CleanEx; HS_SLC2A1; -.
DR Genevestigator; P11166; -.
DR GO; GO:0016323; C:basolateral plasma membrane; IEA:Ensembl.
DR GO; GO:0005901; C:caveola; IEA:Ensembl.
DR GO; GO:0005911; C:cell-cell junction; IEA:Ensembl.
DR GO; GO:0030864; C:cortical actin cytoskeleton; IDA:UniProtKB.
DR GO; GO:0001939; C:female pronucleus; IEA:Ensembl.
DR GO; GO:0016021; C:integral to membrane; IEA:UniProtKB-KW.
DR GO; GO:0042470; C:melanosome; IEA:UniProtKB-SubCell.
DR GO; GO:0030496; C:midbody; IDA:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0055056; F:D-glucose transmembrane transporter activity; IEA:Ensembl.
DR GO; GO:0033300; F:dehydroascorbic acid transporter activity; IEA:Ensembl.
DR GO; GO:0005355; F:glucose transmembrane transporter activity; TAS:ProtInc.
DR GO; GO:0043621; F:protein self-association; IDA:UniProtKB.
DR GO; GO:0042910; F:xenobiotic transporter activity; IEA:Ensembl.
DR GO; GO:0042149; P:cellular response to glucose starvation; IEA:Ensembl.
DR GO; GO:0006112; P:energy reserve metabolic process; TAS:Reactome.
DR GO; GO:0019852; P:L-ascorbic acid metabolic process; TAS:Reactome.
DR GO; GO:0006461; P:protein complex assembly; IDA:UniProtKB.
DR GO; GO:0050796; P:regulation of insulin secretion; TAS:Reactome.
DR GO; GO:0006970; P:response to osmotic stress; IEA:Ensembl.
DR InterPro; IPR002439; Glu_transpt_1.
DR InterPro; IPR020846; MFS_dom.
DR InterPro; IPR016196; MFS_dom_general_subst_transpt.
DR InterPro; IPR005828; Sub_transporter.
DR InterPro; IPR003663; Sugar/inositol_transpt.
DR InterPro; IPR005829; Sugar_transporter_CS.
DR Pfam; PF00083; Sugar_tr; 1.
DR PRINTS; PR01190; GLUCTRSPORT1.
DR PRINTS; PR00171; SUGRTRNSPORT.
DR SUPFAM; SSF103473; SSF103473; 2.
DR TIGRFAMs; TIGR00879; SP; 1.
DR PROSITE; PS50850; MFS; 1.
DR PROSITE; PS00216; SUGAR_TRANSPORT_1; 1.
DR PROSITE; PS00217; SUGAR_TRANSPORT_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Cell membrane; Complete proteome;
KW Direct protein sequencing; Disease mutation; Dystonia; Epilepsy;
KW Glycoprotein; Membrane; Phosphoprotein; Reference proteome;
KW Sugar transport; Transmembrane; Transmembrane helix; Transport.
FT CHAIN 1 492 Solute carrier family 2, facilitated
FT glucose transporter member 1.
FT /FTId=PRO_0000050338.
FT TOPO_DOM 1 12 Cytoplasmic (Potential).
FT TRANSMEM 13 33 Helical; Name=1; (Potential).
FT TOPO_DOM 34 66 Extracellular (Potential).
FT TRANSMEM 67 87 Helical; Name=2; (Potential).
FT TOPO_DOM 88 95 Cytoplasmic (Potential).
FT TRANSMEM 96 116 Helical; Name=3; (Potential).
FT TOPO_DOM 117 126 Extracellular (Potential).
FT TRANSMEM 127 147 Helical; Name=4; (Potential).
FT TOPO_DOM 148 155 Cytoplasmic (Potential).
FT TRANSMEM 156 176 Helical; Name=5; (Potential).
FT TOPO_DOM 177 185 Extracellular (Potential).
FT TRANSMEM 186 206 Helical; Name=6; (Potential).
FT TOPO_DOM 207 271 Cytoplasmic (Potential).
FT TRANSMEM 272 292 Helical; Name=7; (Potential).
FT TOPO_DOM 293 307 Extracellular (Potential).
FT TRANSMEM 308 328 Helical; Name=8; (Potential).
FT TOPO_DOM 329 337 Cytoplasmic (Potential).
FT TRANSMEM 338 358 Helical; Name=9; (Potential).
FT TOPO_DOM 359 371 Extracellular (Potential).
FT TRANSMEM 372 392 Helical; Name=10; (Potential).
FT TOPO_DOM 393 401 Cytoplasmic (Potential).
FT TRANSMEM 402 422 Helical; Name=11; (Potential).
FT TOPO_DOM 423 429 Extracellular (Potential).
FT TRANSMEM 430 450 Helical; Name=12; (Potential).
FT TOPO_DOM 451 492 Cytoplasmic (Potential).
FT REGION 279 281 Defines substrate specificity (By
FT similarity).
FT SITE 411 411 Not glycosylated.
FT MOD_RES 1 1 N-acetylmethionine.
FT MOD_RES 478 478 Phosphothreonine.
FT MOD_RES 490 490 Phosphoserine.
FT CARBOHYD 45 45 N-linked (GlcNAc...).
FT VARIANT 34 34 N -> I (in GLUT1DS2).
FT /FTId=VAR_054755.
FT VARIANT 34 34 N -> S (in GLUT1DS1; 55% of wild-type
FT glucose uptake activity).
FT /FTId=VAR_054756.
FT VARIANT 34 34 N -> Y (in GLUT1DS1).
FT /FTId=VAR_065206.
FT VARIANT 66 66 S -> F (in GLUT1DS1).
FT /FTId=VAR_013283.
FT VARIANT 91 91 G -> D (in GLUT1DS1; significantly
FT decreases the transport of 3-O-methyl-D-
FT glucose).
FT /FTId=VAR_013182.
FT VARIANT 92 92 R -> W (in GLUT1DS2).
FT /FTId=VAR_069077.
FT VARIANT 93 93 R -> W (in GLUT1DS2).
FT /FTId=VAR_065207.
FT VARIANT 95 95 S -> I (in GLUT1DS2).
FT /FTId=VAR_065208.
FT VARIANT 96 96 M -> V (in GLUT1DS1).
FT /FTId=VAR_065209.
FT VARIANT 126 126 R -> C (in GLUT1DS1, GLUT1DS2 and DYT9;
FT reduced transporter activity).
FT /FTId=VAR_054757.
FT VARIANT 126 126 R -> H (in GLUT1DS1; significantly
FT decreases the transport of 3-O-methyl-D-
FT glucose and dehydroascorbic acid; 57% of
FT wild-type glucose uptake activity).
FT /FTId=VAR_013183.
FT VARIANT 126 126 R -> L (in GLUT1DS1; compound
FT heterozygote with V-256).
FT /FTId=VAR_013184.
FT VARIANT 130 130 G -> S (in GLUT1DS1; 75% of wild-type
FT glucose uptake activity).
FT /FTId=VAR_054758.
FT VARIANT 146 146 E -> K (in GLUT1DS1).
FT /FTId=VAR_013284.
FT VARIANT 153 153 R -> C (in GLUT1DS1; 44% of wild-type
FT glucose uptake activity).
FT /FTId=VAR_054759.
FT VARIANT 153 153 R -> H (in GLUT1DS2).
FT /FTId=VAR_065210.
FT VARIANT 155 155 A -> V (in GLUT1DS1).
FT /FTId=VAR_065211.
FT VARIANT 165 165 V -> I (in GLUT1DS2).
FT /FTId=VAR_065212.
FT VARIANT 169 169 Missing (in GLUT1DS1; 48% of wild-type
FT glucose uptake activity).
FT /FTId=VAR_054760.
FT VARIANT 212 212 R -> C (in GLUT1DS1 and DYT9).
FT /FTId=VAR_065213.
FT VARIANT 212 212 R -> H (in GLUT1DS1).
FT /FTId=VAR_065214.
FT VARIANT 223 223 R -> P (in EIG12; mild phenotype; reduced
FT transporter activity).
FT /FTId=VAR_065215.
FT VARIANT 223 223 R -> W (in GLUT1DS1).
FT /FTId=VAR_065216.
FT VARIANT 232 232 R -> C (in EIG12; the mutant protein is
FT expressed at the cell surface but has
FT mildly decreased glucose uptake (70%)
FT compared to wild-type).
FT /FTId=VAR_069078.
FT VARIANT 256 256 K -> E (in GLUT1DS1; compound
FT heterozygote with L-126).
FT /FTId=VAR_013185.
FT VARIANT 275 275 A -> T (in GLUT1DS2; the mutation
FT decreases glucose transport but does not
FT affect cation permeability).
FT /FTId=VAR_054761.
FT VARIANT 282 285 Missing (in GLUT1DS2; accompanied by
FT hemolytic anemia and altered erythrocyte
FT ion concentrations; the mutation
FT decreases glucose transport and causes a
FT cation leak that alteres intracellular
FT concentrations of sodium potassium and
FT calcium).
FT /FTId=VAR_054762.
FT VARIANT 292 292 Y -> YY (in GLUT1DS1).
FT /FTId=VAR_069079.
FT VARIANT 294 294 S -> P (in GLUT1DS2).
FT /FTId=VAR_065784.
FT VARIANT 295 295 T -> M (in GLUT1DS1; 75% of wild-type
FT glucose uptake activity).
FT /FTId=VAR_054763.
FT VARIANT 303 303 V -> L (found in a patient with GLUT1
FT deficiency syndrome).
FT /FTId=VAR_065217.
FT VARIANT 310 310 T -> I (in GLUT1DS1).
FT /FTId=VAR_013285.
FT VARIANT 314 314 G -> S (in GLUT1DS2; the mutation
FT decreases glucose transport but does not
FT affect cation permeability).
FT /FTId=VAR_054764.
FT VARIANT 317 317 N -> T (in GLUT1DS2).
FT /FTId=VAR_065218.
FT VARIANT 324 324 S -> L (in GLUT1DS2; mild phenotype;
FT reduced transporter activity).
FT /FTId=VAR_065219.
FT VARIANT 329 329 E -> Q (in GLUT1DS1).
FT /FTId=VAR_065220.
FT VARIANT 333 333 R -> Q (in GLUT1DS1 and GLUT1DS2).
FT /FTId=VAR_065221.
FT VARIANT 333 333 R -> W (in GLUT1DS1; 43% of wild-type
FT glucose uptake activity).
FT /FTId=VAR_013286.
FT VARIANT 382 382 G -> D (in GLUT1DS1).
FT /FTId=VAR_065222.
FT VARIANT 405 405 A -> D (in GLUT1DS1).
FT /FTId=VAR_065223.
FT VARIANT 468 468 R -> W (in GLUT1DS1).
FT /FTId=VAR_069080.
FT VARIANT 485 485 P -> L (in GLUT1DS1).
FT /FTId=VAR_065224.
FT CONFLICT 25 26 Missing (in Ref. 2; BAF85480).
FT CONFLICT 95 95 S -> L (in Ref. 2; BAF85480).
FT CONFLICT 152 152 L -> F (in Ref. 1; AAA52571).
FT HELIX 6 30
FT HELIX 31 33
FT HELIX 34 39
FT HELIX 48 50
FT STRAND 51 53
FT STRAND 56 58
FT HELIX 61 89
FT HELIX 92 112
FT TURN 119 121
FT HELIX 122 147
FT STRAND 149 151
FT HELIX 152 168
FT HELIX 170 181
FT HELIX 186 188
FT HELIX 189 206
FT TURN 212 214
FT STRAND 220 223
FT TURN 227 229
FT TURN 231 233
FT HELIX 254 260
FT HELIX 265 291
FT TURN 292 294
FT HELIX 305 329
FT HELIX 336 356
FT STRAND 358 360
FT HELIX 361 374
FT HELIX 376 378
FT TURN 380 384
FT HELIX 385 391
FT HELIX 395 397
FT HELIX 399 421
FT HELIX 431 470
FT STRAND 478 481
FT HELIX 485 489
SQ SEQUENCE 492 AA; 54084 MW; E71E1C6BD1B00B1E CRC64;
MEPSSKKLTG RLMLAVGGAV LGSLQFGYNT GVINAPQKVI EEFYNQTWVH RYGESILPTT
LTTLWSLSVA IFSVGGMIGS FSVGLFVNRF GRRNSMLMMN LLAFVSAVLM GFSKLGKSFE
MLILGRFIIG VYCGLTTGFV PMYVGEVSPT ALRGALGTLH QLGIVVGILI AQVFGLDSIM
GNKDLWPLLL SIIFIPALLQ CIVLPFCPES PRFLLINRNE ENRAKSVLKK LRGTADVTHD
LQEMKEESRQ MMREKKVTIL ELFRSPAYRQ PILIAVVLQL SQQLSGINAV FYYSTSIFEK
AGVQQPVYAT IGSGIVNTAF TVVSLFVVER AGRRTLHLIG LAGMAGCAIL MTIALALLEQ
LPWMSYLSIV AIFGFVAFFE VGPGPIPWFI VAELFSQGPR PAAIAVAGFS NWTSNFIVGM
CFQYVEQLCG PYVFIIFTVL LVLFFIFTYF KVPETKGRTF DEIASGFRQG GASQSDKTPE
ELFHPLGADS QV
//

MIM 138140
*RECORD*
*FIELD* NO
138140
*FIELD* TI
*138140 SOLUTE CARRIER FAMILY 2 (FACILITATED GLUCOSE TRANSPORTER), MEMBER
1; SLC2A1
read more;;GLUCOSE TRANSPORTER 1; GLUT; GLUT1;;
ERYTHROCYTE/HEPATOMA GLUCOSE TRANSPORTER
*FIELD* TX

DESCRIPTION

The GLUT1 (HepG2) gene encodes the major glucose transporter in brain,
placenta, and erythrocytes (Baroni et al., 1992).

CLONING

Mueckler et al. (1985) isolated a cDNA corresponding to human GLUT1 from
human HepG2 hepatoma cells. The deduced amino acid sequence indicates
that this protein lacks a signal sequence and possesses 12 potential
membrane-spanning domains. The amino terminus, carboxyl terminus, and a
highly hydrophilic domain in the center of the protein ware all
predicted to lie on the cytoplasmic face of the cell.

Wang et al. (2000) stated that the SLC2A1 gene encodes a 492-amino acid
protein with 97 to 98% identity between human, rat, rabbit, and pig
sequences.

GENE STRUCTURE

Wang et al. (2000) stated the SLC2A1 gene contains 10 exons and spans
approximately 35 kb.

MAPPING

Wang et al. (2005) stated that the SLC2A1 gene maps to chromosome
1p34.2.

Shows et al. (1987) mapped the SLC2A1 gene to chromosome 1p35-p31.3 by
in situ hybridization and by Southern blot analysis of somatic cell
hybrids. They concluded that the most likely location of SLC2A1 is in
1p33.

Ardinger et al. (1987) found linkage between Rh and a DNA polymorphism
for GLUT (theta = 0.21; lod = 3.54). Multipoint analysis indicated that
the order of the loci is probably RH--3--ALPL--12--GLUT--23--PGM1, with
the interlocus intervals as percent recombination in males (female rate
about 2.8 times the male rate). Xiang et al. (1987) described a RFLP of
the GLUT locus.

GENE FUNCTION

The high metabolic requirements of the mammalian central nervous system
require specialized structures for the facilitated transport of
nutrients across the blood-brain barrier. The facilitative glucose
transporter GLUT1 is expressed on endothelial cells at the blood-brain
barrier and is responsible for glucose entry into the brain (Agus et
al., 1997). Stereo-specific high-capacity carriers, including those that
recognize glucose, are key components of this barrier, which also
protects the brain against noxious substances.

Agus et al. (1997) provided evidence that GLUT1 also transports
dehydroascorbic acid (the oxidized form of vitamin C) into the brain.
Vitamin C concentrations in the brain exceed those in blood by 10 fold.
In both tissues, the vitamin is present primarily in the reduced form,
ascorbic acid. Agus et al. (1997) showed that ascorbic acid is not able
to cross the blood-brain barrier; in contrast, dehydroascorbic acid
readily enters the brain and is retained in the brain tissue in the form
of ascorbic acid. Transport of dehydroascorbic acid into the brain is
inhibited by D-glucose, but not by L-glucose. Thus, transport of
dehydroascorbic acid by GLUT1 is a mechanism by which the brain acquires
vitamin C. The studies of Agus et al. (1997) pointed to the oxidation of
ascorbic acid as a potentially important regulatory step in accumulation
of the vitamin by the brain. These results have implications for
increasing antioxidant potential in the central nervous system.

Lazar et al. (1999) studied the expression of 4 thyroid-specific genes
(sodium-iodide symporter (NIS, or SLC5A5; 601843), thyroid peroxidase
(TPO; 606765), thyroglobulin (TG; 188450), and thyroid-stimulating
hormone receptor (TSHR; 603372)) as well as the gene encoding GLUT1 in
90 human thyroid tissues. mRNAs were extracted from 43 thyroid
carcinomas (38 papillary and 5 follicular), 24 cold adenomas, 5 Graves
thyroid tissues, 8 toxic adenomas, and 5 hyperplastic thyroid tissues; 5
normal thyroid tissues were used as reference. Expression of the GLUT1
gene was increased in 1 of 24 (4%) adenomas and in 8 of 43 (19%) thyroid
carcinomas. 3 patients with normal GLUT1 expression had 131-I uptake in
metastases, whereas the other 3 patients with increased GLUT1 gene
expression had no detectable 131-I uptake. The authors concluded that an
increased expression of GLUT1 in some malignant tumors may suggest a
role for glucose-derivative tracers to detect in vivo thyroid cancer
metastases by positron-emission tomography scanning.

Translational repression of GLUT1 in glioblastoma multiforme (GBM;
137800) is mediated by a specific RNA-binding protein that interacts
with an AU-rich response element in the 3-prime UTR of the GLUT1
transcript. Hamilton et al. (1999) showed that HNRNPA2 (600124) and
HNRNPL (603083) bound the 3-prime UTR of GLUT1 mRNA. Induction of brain
ischemia in rats or hypoglycemic stress in 293 cells increased GLUT1
expression via mRNA stability. Polysomes isolated from ischemic rat
brains or hypoglycemic 293 cells showed loss of HNRNPA2 and HNRNPL,
suggesting that reduced levels of these RNA-binding proteins results in
GLUT1 mRNA stability.

Manel et al. (2003) showed that the receptor-binding domains of the
human T-cell leukemia virus (HTLV)-1 and -2 envelope glycoproteins
inhibited glucose transport by interacting with GLUT1, the ubiquitous
vertebrate glucose transporter. Receptor binding and HTLV
envelope-driven infection were selectively inhibited when glucose
transport or GLUT1 expression were blocked by cytochalasin B or siRNAs,
respectively. Furthermore, ectopic expression of GLUT1, but not the
related transporter GLUT3 (138170), restored HTLV infection abrogated by
either GLUT1 siRNAs or interfering HTLV envelope glycoproteins. Manel et
al. (2003) concluded that GLUT1 is a receptor for HTLV and suggested
that perturbations in glucose metabolism resulting from interactions of
HTLV envelope glycoproteins with GLUT1 are likely to contribute to
HTLV-associated disorders.

Montel-Hagen et al. (2008) stated that, of all human cell lineages,
erythrocytes express the highest level of GLUT1, with more than 200,000
molecules per cell. They showed that GLUT1 preferentially transported
L-dehydroascorbic acid (DHA) rather than glucose in human erythrocytes.
This switch from glucose to DHA was associated with induction of
stomatin (EPB72; 133090), an integral erythrocyte membrane protein.
Accordingly, in a patient with overhydrated hereditary stomatocytosis
(185000), a disorder characterized by low stomatin levels, DHA transport
was decreased by 50%, while glucose uptake was significantly increased.
Montel-Hagen et al. (2008) found that erythrocyte-specific GLUT1
expression and DHA transport are specific traits of vitamin C-deficient
mammalian species, encompassing only higher primates, guinea pigs, and
fruit bats. Adult mouse erythrocytes expressed Glut4 rather than Glut1
and did not transport DHA. Montel-Hagen et al. (2008) concluded that
induction of GLUT1 and stomatin during erythroid differentiation is a
compensatory mechanism in mammals unable to synthesize vitamin C.

By studying the transcriptomes of paired colorectal cancer cell lines
that differed only in the mutational status of their KRAS (190070) or
BRAF (164757) genes, Yun et al. (2009) found that GLUT1 was 1 of 3 genes
consistently upregulated in cells with KRAS or BRAF mutations. The
mutant cells exhibited enhanced glucose uptake and glycolysis and
survived in low-glucose conditions, phenotypes that all required GLUT1
expression. In contrast, when cells with wildtype KRAS alleles were
subjected to a low-glucose environment, very few cells survived. Most
surviving cells expressed high levels of GLUT1, and 4% of these
survivors had acquired KRAS mutations not present in their parents. The
glycolysis inhibitor 3-bromopyruvate preferentially suppressed the
growth of cells with KRAS or BRAF mutations. Yun et al. (2009) concluded
that, taken together, these data suggested that glucose deprivation can
drive the acquisition of KRAS pathway mutations in human tumors.

- Role in Diabetes

Insulin increases glucose uptake in responsive cells by inducing the
rapid translocation of glucose transporters from an intracellular
storage pool to the plasma membrane. Li et al. (1988) demonstrated a
significantly increased frequency of the X1 allele (the 6.2 kb fragment
recognized by the human glucose transporter cDNA) among 89 patients with
noninsulin-dependent diabetes mellitus (NIDDM; 125853) from 3 different
ethnic populations. They suggested that the observed association may
reflect linkage of the X1 allele to a putative diabetogenic locus on
chromosome 1; they hypothesized that the glucose transporter gene itself
may be a major genetic determinant for noninsulin-dependent diabetes
mellitus. Baroni et al. (1992) extended the data suggesting an
association between polymorphic markers at the GLUT1 locus and NIDDM in
the Italian population studied.

Shepherd and Kahn (1999) discussed in detail the role of glucose
transporters in insulin action and the implications for insulin
resistance and diabetes mellitus. In their Table 1, they presented 5
forms of GLUT (GLUT1-5) and gave the approximate K(m) for glucose and
the tissue distribution and characteristics of each. They pointed out
that GLUT4 (138190) is the main insulin-responsive glucose transporter,
being located primarily in muscle cells and adipocytes. The role of
GLUT4 in the mechanism of effectiveness of drug therapy for diabetes was
reviewed.

Lohmueller et al. (2003) performed a metaanalysis of 301 published
genetic association studies covering 25 different reported associations.
For 8 of the associations, pooled analysis of follow-up studies yielded
statistically significant replication of the first report, with modest
estimated genetic effects. One of these 8 was the association between
type II diabetes and an XbaI RFLP (6.2-kb allele) of the SLC2A1 gene, as
first reported by Li et al. (1988).

MOLECULAR GENETICS

- GLUT1 Deficiency Syndrome 1

In patients with a transport defect of glucose across the blood-brain
barrier, consistent with GLUT1 deficiency syndrome-1 (GLUT1DS1; 606777),
Seidner et al. (1998) identified heterozygous mutations in the SLC2A1
gene (138140.0001-138140.0003). Two of the patients had been reported by
De Vivo et al. (1991).

Klepper et al. (2001) reported a father and 2 children from separate
marriages who were affected by GLUT1 deficiency, and confirmed autosomal
dominant transmission by identifying a heterozygous mutation in the
GLUT1 gene (G91D; 138140.0006). The father developed generalized
tonic-clonic seizures and myoclonic seizures at age 3 years. As an
adult, he had mild mental retardation, depression, and migraine. One
daughter had mild spastic diplegia at age 9 months and showed
developmental delay over the next 2 years. At age 3, she developed
complex partial seizures. At age 10, she had moderate mental
retardation, cerebellar ataxia, and mild pyramidal signs of the legs.
The second daughter showed developmental delay, spastic diplegia, and
generalized tonic-clonic seizures at age 2 years. Physical exam at age
22 years revealed moderate mental retardation, cerebellar ataxia, and
spastic tetraplegia that predominantly involved the legs. The 2
daughters both had hypoglycorrhachia.

Among 16 patients with GLUT1 deficiency, Wang et al. (2005) identified
16 different mutations in the SLC2A1 gene; 14 of the mutations were
novel.

- GLUT1 Deficiency Syndrome 2

Overweg-Plandsoen et al. (2003) reported a 6-year-old boy with GLUT1
deficiency who had delayed psychomotor development, moderate mental
retardation, horizontal nystagmus, dysarthria, limb ataxia,
hyperreflexia, and dystonic posturing of the limbs, consistent with
GLUT1 deficiency syndrome-2 (GLUT1DS2; 612126). He had never had
seizures. The motor activity and coordination fluctuated throughout the
day, which was unrelated to food intake. Laboratory studies showed
hypoglycorrhachia and low CSF lactate. Genetic analysis identified a de
novo heterozygous mutation in the GLUT1 gene (N34I; 138140.0011). A
ketogenic diet helped with the motor symptoms.

In affected members of 3 unrelated families with paroxysmal
exercise-induced dyskinesias (PED) consistent with GLUT1DS2, Weber et
al. (2008) identified 3 different heterozygous mutations in the SLC2A1
gene (138140.0008-138140.0010). The phenotype was characterized by
childhood onset of paroxysmal exertion-induced dyskinesias. One family
also had hematologic abnormalities consistent with hemolytic anemia.
Based on these findings and brain imaging studies, Weber et al. (2008)
concluded that the dyskinesias resulted from an exertion-induced energy
deficit causing episodic dysfunction in the basal ganglia. The hemolysis
observed in 1 family was demonstrated in vitro in Xenopus oocytes and
human erythrocytes to result from alterations in intracellular
electrolytes caused by a cation leak through mutant GLUT1.

In affected members of a large Belgian family segregating PED and
epilepsy, Suls et al. (2008) identified a heterozygous missense mutation
in the GLUT1 gene (S95I; 138140.0012).

Schneider et al. (2009) identified 2 different de novo heterozygous
mutations in the GLUT1 gene (see, e.g., 138140.0015) in 2 of 10
unrelated Caucasian patients with paroxysmal exercise-induced
dyskinesias. One of the patients had childhood onset of absence
epilepsy.

- Susceptibility to Idiopathic Generalized Epilepsy 12

Suls et al. (2009) identified heterozygous mutations (see, e.g.,
138140.0020) in the SLC2A1 gene in 4 (12%) of 34 patients with
early-onset absence epilepsy before age 4 years (EIG12; 614847). CSF
glucose levels were not available from any of the patients. One of the
patients had no additional abnormalities and normal development.
However, clinical review of these patients after diagnosis showed that 3
had mild to moderate mental retardation, 2 had mild ataxia, and 1 had
myoclonus and exercise-induced paroxysmal dyskinesia. None had
microcephaly. Two patients inherited missense mutations from parents
with later-onset absence epilepsy. The findings further expanded the
phenotype associated with SLC2A1 mutations, and suggested that patients
with onset of absence seizures before age 4 years in particular should
be screened for mutations in this gene.

In 8 affected members of an Italian family with idiopathic generalized
epilepsy-12 manifest mainly as childhood-onset absence seizures, Striano
et al. (2012) identified a heterozygous mutation in the SLC2A1 gene
(R232C; 138140.0019). The mutation was also found in 4 healthy adult
family members, yielding a reduced penetrance of 67%. In vitro
functional studies showed that the mutant protein was expressed at the
cell surface but had mildly decreased glucose uptake (70%) compared to
wildtype. The mutation was found in 1 of 95 families with EIG. These
findings suggested that GLUT1 deficiency is a rare cause of typical EIG,
and also expanded the phenotypic spectrum associated with mutations in
the SLC2A1 gene.

- Dystonia 9

In affected members of the family with autosomal dominant dystonia-9
(DYT9; 601042) originally reported by Auburger et al. (1996), Weber et
al. (2011) identified a heterozygous mutation in the SLC2A1 gene (R232C;
138140.0018). Two Australian brothers with the disorder carried a
different heterozygous mutation (R126C; 138140.0014). The disorder was
characterized by childhood onset of paroxysmal choreoathetosis and
progressive spastic paraplegia. Most showed some degree of cognitive
impairment. Other variable features included seizures, migraine
headaches, and ataxia.

ANIMAL MODEL

In mouse preimplantation embryos, Moley et al. (1998) found that glucose
uptake was significantly lowered in embryos from diabetic mice compared
to control mice. Diabetic embryos had significantly decreased levels of
Glut1 mRNA and protein levels, indicating a decrease in glucose
utilization directly related to a decrease in glucose transport. Chi et
al. (2000) found that decreased Glut1 expression and function resulted
in a high rate of apoptosis at the murine blastocyst stage via a Bax
(600040)-dependent apoptotic cascade. The findings suggested that
maternal hyperglycemia induces a cell death signal by decreasing glucose
transport. This results in a loss of key progenitor cells during the
blastocyst stage, which may manifest as embryonic resorption or
malformation. In transgenic mice generated using antisense Glut1, Heilig
et al. (2003) found reduction of glucose uptake, by 50% in presumed
heterozygotes and 95% in presumed homozygotes, as well as developmental
malformations associated with maternal diabetes, including intrauterine
growth retardation, anencephaly, microphthalmia, and caudal regression
syndrome, an impaired development of the hind portion of the embryo.
Macrosomia was not observed. The homozygous Glut1 mutant phenotype was
lethal during gestation, and reduced embryonic Glut1 was associated with
apoptosis. Heilig et al. (2003) suggested that GLUT1 deficiency causes a
decrease in embryonic glucose uptake and apoptosis, which may be
involved in diabetic embryopathy.

Wang et al. (2006) found that mice with targeted heterozygous disruption
of the Glut1 gene developed spontaneous epileptiform discharges,
impaired motor activity, incoordination, hypoglycorrhachia, decreased
brain weight (microencephaly), decreased brain glucose uptake, and
decreased expression of Glut1 in the brain (66% of controls). Homozygous
mutant mice were embryonic lethal. Wang et al. (2006) suggested that
Glut1 +/- mice mimics the classic human presentation of GLUT1 deficiency
and can be used as an animal model to examine the pathophysiology of the
disorder in vivo.

In zebrafish, Zheng et al. (2010) found that knockdown of Glut1 resulted
in impaired development of cerebral endothelial cells, disruption of the
junctional barrier of the blood-brain barrier, impaired cerebral
circulation, and vasogenic brain edema. The authors concluded that Glut1
plays a role in the development of cerebral endothelial cells with
properties of the blood-brain barrier.

*FIELD* AV
.0001
GLUT1 DEFICIENCY SYNDROME 1
SLC2A1, DEL

In a patient originally reported by De Vivo et al. (1991) with severe
manifestations related to a demonstrable defect in glucose transport
across the blood-brain barrier (606777), Seidner et al. (1998)
identified a heterozygous deletion of the GLUT1 gene. The deletion
appeared to be a de novo mutation.

Wang et al. (2000) identified 1 patient who was hemizygous for the GLUT1
gene.

.0002
GLUT1 DEFICIENCY SYNDROME 1
SLC2A1, LYS456TER

In a patient with severe clinical consequences of a defect in the
transport of glucose across the blood-brain barrier (606777), Seidner et
al. (1998) identified a heterozygous 1545A-T transversion in the SLC2A1
gene, resulting in a lys456-to-ter (K456X) substitution.

.0003
GLUT1 DEFICIENCY SYNDROME 1
SLC2A1, TYR449TER

In a patient originally reported by De Vivo et al. (1991) with severe
clinical consequences of a defect in the transport of glucose across the
blood-brain barrier (606777), Seidner et al. (1998) identified a
heterozygous 1526C-A transversion in the SLC2A1 gene, resulting in a
tyr449-to-ter (Y449X) substitution.

.0004
GLUT1 DEFICIENCY SYNDROME 1, AUTOSOMAL RECESSIVE
SLC2A1, LYS256VAL

In a patient with blood-brain barrier glucose transport defect (606777),
Wang et al. (2000) identified compound heterozygosity for 2 mutations in
the SLC2A1 gene: a 945A-G transition in exon 5, resulting in a
lys256-to-val (K256V) substitution on the maternally derived allele, and
a 556G-T transversion in exon 4, resulting in an arg126-to-leu (R126L;
138140.0005) substitution on the paternally derived allele. In addition
to having no noticeable symptoms of GLUT1 deficiency syndrome, the
mother had no defect in erythrocyte glucose uptake in vitro. Wang et al.
(2000) raised the possibility of a synergistic effect of these 2
mutations when present in compound heterozygous state.

Rotstein et al. (2010) provided further details of the patient with
autosomal recessive GLUT1 deficiency syndrome reported by Wang et al.
(2000). He developed recurrent limb stiffening and cyanosis at age 6
weeks. Seizures included tonic eye deviation, staring spells, myoclonic
jerks, and prolonged and refractory generalized tonic-clonic seizures.
He had delayed psychomotor development and progressive microcephaly. CSF
showed hypoglycorrhachia. A ketogenic diet was helpful, but his
developmental quotient was 42 at age 6 years. He had axial hypotonia,
limb spasticity and dystonia, and severe ataxia. The patient's glucose
uptake in red blood cells was 36% of controls. Studies in Xenopus
oocytes showed 3.2% residual activity with the R126L-mutant protein and
12.7% residual activity with the K256V-mutant protein.

.0005
GLUT1 DEFICIENCY SYNDROME 1, AUTOSOMAL RECESSIVE
SLC2A1, ARG126LEU

See 138140.0004 and Wang et al. (2000).

.0006
GLUT1 DEFICIENCY SYNDROME 1
SLC2A1, GLY91ASP

Klepper et al. (2001) reported a father and 2 children from separate
marriages affected by GLUT1 deficiency (606777) who were heterozygous
for a gly91-to-asp (G91D) substitution in the GLUT1 gene. The father
developed generalized tonic-clonic seizures and myoclonic seizures at
age 3 years. As an adult, he had mild mental retardation, depression,
and migraine. One daughter had mild spastic diplegia at age 9 months and
showed developmental delay over the next 2 years. At age 3, she
developed complex partial seizures. At age 10 years, she had moderate
mental retardation, cerebellar ataxia, and mild pyramidal signs of the
legs. The second daughter showed developmental delay, spastic diplegia,
and generalized tonic-clonic seizures at age 2. Physical exam at age 22
years revealed moderate mental retardation, cerebellar ataxia, and
spastic tetraplegia that predominantly involved the legs. The 2
daughters both had hypoglycorrhachia. The G91D amino acid change was
predicted to affect an arg-X-gly-arg-arg motif between helices 2 and 3
that represents a highly conserved cytoplasmic anchor point. The uptake
of 3-O-methyl-D-glucose into erythrocytes was significantly reduced,
suggesting a quantitatively normal, but functionally impaired, GLUT1
protein at the cell membrane.

Klepper et al. (2001) demonstrated that expression of mutant G91D or
G91A in Xenopus oocytes resulted in significantly decreased glucose
transport (by about 40%) compared to wildtype. The mutant proteins were
present at the plasma membrane at levels comparable to wildtype. Klepper
et al. (2001) concluded that the loss of glycine at this position,
rather than the introduction of aspartic acid, was responsible for the
functional consequences observed in these patients.

.0007
GLUT1 DEFICIENCY SYNDROME 1
SLC2A1, ARG126HIS

In affected members of a family with GLUT1 deficiency (606777),
Brockmann et al. (2001) identified a heterozygous arg126-to-his (R126H)
missense mutation in the SLC2A1 gene.

.0008
GLUT1 DEFICIENCY SYNDROME 2
SLC2A1, 12-BP DEL, NT1022

In 4 affected members of a family with paroxysmal exertion-induced
dyskinesia and hemolytic anemia (612126), Weber et al. (2008) identified
a heterozygous 12-bp deletion (1022_1033del) in exon 6 of the SLC2A1
gene, resulting in a loss of 4 amino acids within the seventh
transmembrane segment, which contains a highly conserved portion of the
pore-forming region. The mutation was not detected in 150 controls.
Clinical features included childhood onset of episodic involuntary
exertion-induced dystonic, choreoathetotic, and ballistic movements. In
addition, all affected family members had a history of macrocytic
hemolytic anemia with reticulocytosis. Two patients had seizures and 1
had decreased cognitive function with an IQ of 77. In vitro functional
expression studies in Xenopus oocytes and human erythrocytes showed that
the mutation decreased glucose transport and caused a cation leak that
altered intracellular concentrations of sodium, potassium, and calcium.
Based on these findings and brain imaging studies, Weber et al. (2008)
concluded that the dyskinesias resulted from an exertion-induced energy
deficit causing episodic dysfunction in the basal ganglia. The hemolysis
resulted from alterations in intracellular electrolytes caused by a
cation leak through mutant GLUT1.

.0009
GLUT1 DEFICIENCY SYNDROME 2
SLC2A1, GLY314SER

In 5 affected members of a family with GLUT1 deficiency syndrome-2
(612126), Weber et al. (2008) identified a heterozygous 1119G-A
transition in the SLC2A1 gene, resulting in a gly314-to-ser (G314S)
substitution in the eighth transmembrane segment. The phenotype was
characterized by childhood-onset paroxysmal exertion-induced dyskinesia
with epilepsy with absences or complex partial seizures, mild learning
disabilities, and an irritable behavior with increased impulsivity in 6
affected members. Hematologic abnormalities were not observed. The
mutation was also identified in 2 unaffected family members, indicating
decreased penetrance. The mutation was not identified in 150 controls.
In vitro functional expression studies showed that the mutation
decreased glucose transport but did not affect cation permeability.

.0010
GLUT1 DEFICIENCY SYNDROME 2
SLC2A1, ALA275THR

In 5 affected members of a family with GLUT1 deficiency syndrome-2
(612126), Weber et al. (2008) identified a heterozygous 1002G-A
transition in the SLC2A1 gene, resulting in an ala275-to-thr (A275T)
substitution at the cytoplasmic end of transmembrane segment 7. The
mutation was not identified in 150 controls. In vitro functional
expression studies showed that the mutation decreased glucose transport
but did not affect cation permeability.

.0011
GLUT1 DEFICIENCY SYNDROME 2
SLC2A1, ASN34ILE

In a 6-year-old boy with GLUT1 deficiency syndrome-2 (612126),
Overweg-Plandsoen et al. (2003) identified a de novo heterozygous 280A-T
transversion in exon 2 of the GLUT1 gene, resulting in an asn34-to-ile
(N34I) substitution in the largest extracellular loop connecting
transmembrane domains 1 and 2. He had an atypical phenotype in that he
never had seizures. Clinical features included delayed psychomotor
development, moderate mental retardation, dysarthria, limb ataxia,
hyperreflexia, and dystonic posturing of the arms. The motor activity
and coordination fluctuated throughout the day, which was unrelated to
food intake. A ketogenic diet helped with the motor symptoms.

.0012
GLUT1 DEFICIENCY SYNDROME 2
SLC2A1, SER95ILE

In affected members of a large Belgian family segregating paroxysmal
exercise-induced dyskinesia with or without epilepsy (612126), Suls et
al. (2008) identified a heterozygous ser95-to-ile (S95I) mutation in
exon 4 of the SLC2A1 gene. The mutation resulted from a T-A transversion
and a C-T transition at nucleotides 283 and 284, respectively. The
mutation occurred in the cytosolic loop connecting transmembrane
segments 2 and 3, and was not found in 184 ethnically matched controls.
In vitro functional expression studies in Xenopus oocytes showed that
the S95I mutant protein caused reduced glucose uptake with a decrease of
maximal transport velocity compared to wildtype. Cation permeability was
not affected, and none of the patients had hemolytic anemia.

.0013
GLUT1 DEFICIENCY SYNDROME 2
SLC2A1, ARG93TRP

In a 13-year-old boy with GLUT1 deficiency syndrome-2 (612126), Joshi et
al. (2008) identified a heterozygous mutation in the SLC2A1 gene,
resulting in an arg93-to-trp (R93W) substitution. The patient had an
atypical phenotype, with delayed psychomotor development, early-onset
ataxia, and hyperreflexia. He first developed a seizure disorder at age
11 years, with staring spells, head jerking, eye rolling, and loss of
tone, which progressed to absence, myoclonic, and atonic seizures. His
cognitive and motor skills deteriorated during this period. EEG showed
moderate background slowing. Laboratory studies showed decreased CSF
glucose and lactate, consistent with GLUT1 deficiency syndrome. A
ketogenic diet resulted in complete seizure control with motor and
cognitive improvement.

Rotstein et al. (2009) identified a de novo heterozygous R93W mutation
in a 10-year-old boy with GLUT1 deficiency. At age 2 years, he had onset
of episodic ataxia and slurred speech associated with unilateral muscle
weakness. Laboratory studies showed significantly decreased CSF glucose
levels. He showed gradual cognitive decline, progressive microcephaly,
and ataxia during childhood. Rotstein et al. (2009) noted that the
phenotype in this patient was reminiscent of alternating hemiplegia of
childhood (104290). Studies of patient erythrocytes showed about a 50%
decrease in glucose uptake compared to controls. The R93W substitution
occurs in the first cytosolic loop of the protein.

.0014
GLUT1 DEFICIENCY SYNDROME 1
GLUT1 DEFICIENCY SYNDROME 2, INCLUDED;;
DYSTONIA 9, INCLUDED
SLC2A1, ARG126CYS

In a 22-year-old Italian woman with GLUT1 deficiency syndrome-1
(606777), Zorzi et al. (2008) identified a heterozygous de novo mutation
in the SLC2A1 gene, resulting in an arg126-to-cys (R126C) substitution.
She had delayed psychomotor development, mild mental retardation,
microcephaly, dysarthria, and spasticity. She had onset of complex
partial seizures at age 4 months. At age 10, she developed paroxysmal
exercise-induced leg dystonia. CSF glucose was reduced at 31 mg/dl.

Suls et al. (2009) identified a de novo heterozygous R126C mutation,
resulting from a 376C-T transition in exon 4 of the GLUT1 gene, in a
12-year-old girl who developed absence seizures and myoclonus at age 14
months. She had mild gait ataxia, subtle paroxysmal exercise-induced
dyskinesia, and moderate mental retardation, consistent with GLUT1DS2
(612126). The mutation occurred in a highly conserved region of
transmembrane domain 4, and was not found in 276 control chromosomes. In
vitro functional expression studies in Xenopus oocytes showed that the
mutation resulted in decreased glucose transport without affecting
glucose binding. Mutations in the same codon (R126L; 138140.0005 and
R126H; 138140.0007) have been found in other patients with GLUT1DS1.

Weber et al. (2011) identified a heterozygous R126C mutation in
Australian twin brothers with dystonia-9 (DYT9; 601042) and mental
retardation. Both had onset in early childhood of paroxysmal
choreoathetosis and progressive spastic paraparesis; ataxia was not
observed.

.0015
GLUT1 DEFICIENCY SYNDROME 2
SLC2A1, ARG91TRP

In a 25-year-old Caucasian English woman with GLUT1 deficiency
syndrome-2 (612126), Schneider et al. (2009) identified a de novo
heterozygous 274C-T transition in the SLC2A1 gene, resulting in an
arg91-to-trp (R91W) substitution. The mutation was not found in 382
control chromosomes. The patient developed paroxysmal exercise-induced
dyskinesias in early childhood. She also had absence seizures between
ages 4 and 10 years, and developed migraine with visual aura at age 11.
The migraines were occasionally associated with hemiplegia.

.0016
GLUT1 DEFICIENCY SYNDROME 1, AUTOSOMAL RECESSIVE
SLC2A1, ARG468TRP

In a 6-year-old girl, born of consanguineous Arab parents from a Bedouin
kindred from Qatar, with GLUT1 deficiency syndrome-1 (606777), Klepper
et al. (2009) identified a homozygous 1402C-T transition in exon 10 of
the SLC2A1 gene, resulting in an arg468-to-trp (R468W) substitution. She
was noted to have unsteady ataxic gait at age 18 months, as well as
paroxysmal choreoathetosis. She also had developmental delay and
hypotonia. EEG showed a polymorphic baseline alpha-theta activity with
an isolated monomorphic sharp wave focus. Lumbar puncture showed
hypoglycorrhachia and decreased CSF lactate. Her clinically asymptomatic
2-year-old sister was also homozygous for the mutation; she was found to
have hypoglycorrhachia and decreased CSF lactate. The parents, who were
unaffected, were heterozygous for the mutation. Klepper et al. (2009)
concluded that the mutation was pathogenic, since the affected residue
is highly conserved, is located in the C terminus which is essential for
substrate recognition and transport, and was not found in 120 control
alleles. Klepper et al. (2009) suggested that the unaffected sister who
was homozygous for the mutation was too young for symptom onset. The
findings suggested that GLUT1 deficiency can also be inherited in an
autosomal recessive pattern.

.0017
GLUT1 DEFICIENCY SYNDROME 2
SLC2A1, 3-BP INS, TAT

In a 7-year-old girl with GLUT1 deficiency syndrome-2 (612126),
Perez-Duenas et al. (2009) identified a heterozygous de novo 3-bp
insertion (TAT) in the SLC2A1 gene, resulting in addition of a tyrosine
at codon 292 in the extracellular boundary of the seventh transmembrane
domain, predicted to impair blood-brain glucose flux. She already had
delayed psychomotor development but presented at age 5 years with
episodic flaccidity and loss of ambulation. The episodes continued and
were accompanied by gait ataxia, dysarthria, dyskinesias, and choreic
movements. Milder features included action tremor, upper limb dysmetria,
and ataxia. Brain MRI showed moderately severe supratentorial
cortico-subcortical atrophy, and EEG showed mild diffuse slowing. CSF
glucose was decreased. Institution of a ketogenic diet resulted in
clinical improvement of the movement disorder and increased brain
growth, although cognitive skills did not improve.

.0018
DYSTONIA 9
SLC2A1, ARG212CYS

In affected members of a large German family with dystonia-9 (DYT9;
601042) originally reported by Auburger et al. (1996), Weber et al.
(2011) identified a heterozygous 634C-T transition in the SLC2A1 gene,
resulting in an arg212-to-cys (R212C) substitution in the third
intracellular loop close to the sixth transmembrane segment. The
mutation was not found in 400 control chromosomes. In vitro functional
expression studies showed that the mutant protein had normal expression
at the cell surface, but decreased glucose uptake compared to wildtype.

.0019
EPILEPSY, IDIOPATHIC GENERALIZED, SUSCEPTIBILITY TO, 12
SLC2A1, ARG232CYS

In 8 affected members of an Italian family with idiopathic generalized
epilepsy-12 (EIG12; 614847), Striano et al. (2012) identified a
heterozygous 694C-T transition in the SLC2A1 gene, resulting in an
arg232-to-cys (R232C) substitution at a highly conserved residue in the
third intracellular loop. The mutation was not found in 846 normal
controls. The mutation was also found in 4 healthy adult family members,
yielding a penetrance of 67%. In vitro functional studies showed that
the mutant protein was expressed at the cell surface, but had mildly
decreased glucose uptake (70%) compared to wildtype. The findings
suggested that GLUT1 deficiency is a rare cause of typical EIG, and also
expanded the phenotypic spectrum associated with mutations in the SLC2A1
gene. The age at seizure onset ranged from early childhood to 23 years.
All had generalized seizures, mainly typical absence seizures, and EEG
showed regular, symmetric discharges of 3 to 3.5 Hz spike wave
complexes. Seizures typically remitted 2 to 5 years after onset,
although 1 patient later developed juvenile myoclonic epilepsy. Most
showed a favorable response to pharmacologic treatment. None of the
patients had other neurologic manifestations, including movement
disorders.

.0020
EPILEPSY, IDIOPATHIC GENERALIZED, SUSCEPTIBILITY TO, 12
SLC2A1, ARG223PRO

In a 28-year old woman with idiopathic generalized epilepsy-12 (614847)
manifest as childhood onset of absence seizures at age 3 and generalized
seizures at age 7, Suls et al. (2009) identified a heterozygous 668G-C
transversion in exon 5 of the SLC2A1 gene, resulting in an arg223-to-pro
(R223P) substitution at a residue conserved only in mammals.
Intelligence was normal and she was seizure-free with medication since
age 7. In vitro functional expression studies showed that the mutant
protein had significantly decreased glucose uptake in Xenopus oocytes
compared to controls.

.0021
EPILEPSY, IDIOPATHIC GENERALIZED, SUSCEPTIBILITY TO, 12
SLC2A1, ARG458TRP

In a 30-year-old man with EIG12 (614847), Arsov et al. (2012) identified
a heterozygous c.1372C-T transition in exon 10 of the SLC2A1 gene,
resulting in an arg458-to-trp (R458W) substitution at a highly conserved
residue. In vitro functional expression studies in Xenopus oocytes
showed that the R458W substitution caused a marked reduced in glucose
transport. The patient had onset of childhood absence epilepsy at age 6
and developed paroyxsmal exertional dyskinesia in his teens. He also had
arm dystonia. The patient's father, who also carried the mutation, had
onset of childhood absence seizures at age 7, developed PED as an adult,
and had disabling leg dyskinesia when walking. The father's unaffected
66-year-old sister also carried the mutation, indicating incomplete
penetrance. The proband was identified from a cohort of 504 probands
with IGE who underwent direct sequencing of the SLC2A1 gene. The
mutation was not found in 470 controls and had not previously been
reported in databases of normal human genetic variation.

.0022
EPILEPSY, IDIOPATHIC GENERALIZED, SUSCEPTIBILITY TO, 12
SLC2A1, ASN411SER

In 2 adult brothers with EIG12 (614847), Arsov et al. (2012) identified
a heterozygous c.1232A-G transition in exon 9 of the SLC2A1 gene,
resulting in an asn411-to-ser (N411S) substitution at a highly conserved
residue. In vitro functional expression studies in Xenopus oocytes
showed that the N411S substitution caused a marked reduced in glucose
transport. Both patients developed childhood absence epilepsy at age 6
years; 1 also had juvenile myoclonic epilepsy. The proband was
identified from a cohort of 504 probands with IGE who underwent direct
sequencing of the SLC2A1 gene. The mutation was not found in 470
controls and had not previously been reported in databases of normal
human genetic variation.

*FIELD* SA
Sarkar et al. (1988)
*FIELD* RF
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11. Joshi, C.; Greenberg, C. R.; De Vivo, D.; Wang, D.; Chan-Lui,
W.; Booth, F. A.: GLUT1 deficiency without epilepsy: yet another
case. J. Child Neurol. 23: 832-834, 2008.

12. Klepper, J.; Monden, I.; Guertsen, E.; Voit, T.; Willemsen, M.;
Keller, K.: Functional consequences of the autosomal dominant G272A
mutation in the human GLUT1 gene. FEBS Lett. 498: 104-109, 2001.

13. Klepper, J.; Scheffer, H.; Elsaid, M. F.; Kamsteeg, E.-J.; Leferink,
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14. Klepper, J.; Willemsen, M.; Verrips, A.; Guertsen, E.; Herrmann,
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of GLUT1 deficiency. Hum. Molec. Genet. 10: 63-68, 2001.

15. Lazar, V.; Bidart, J.-M.; Caillou, B.; Mahe, C.; Lacroix, L.;
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16. Li, S. R.; Baroni, M. G.; Oelbaum, R. S.; Stock, J.; Galton, D.
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Note: Originally Volume II.

17. Lohmueller, K. E.; Pearce, C. L.; Pike, M.; Lander, E. S.; Hirschhorn,
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18. Manel, N.; Kim, F. J.; Kinet, S.; Taylor, N.; Sitbon, M.; Battini,
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19. Moley, K. H.; Chi, M. M.-Y.; Mueckler, M. M.: Maternal hyperglycemia
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20. Montel-Hagen, A.; Kinet, S.; Manel, N.; Mongellaz, C.; Prohaska,
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21. Mueckler, M.; Caruso, C.; Baldwin, S. A.; Panico, M.; Blench,
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22. Overweg-Plandsoen, W. C. G.; Groener, J. E. M.; Wang, D.; Onkenhout,
W.; Brouwer, O. F.; Bakker, H. D.; De Vivo, D. C.: GLUT-1 deficiency
without epilepsy--an exceptional case. J. Inherit. Metab. Dis. 26:
559-563, 2003.

23. Perez-Duenas, B.; Prior, C.; Ma, Q.; Fernandez-Alvarez, E.; Setoain,
X.; Artuch, R.; Pascual, J. M.: Childhood chorea with cerebral hypotrophy:
a treatable GLUT1 energy failure syndrome. Arch. Neurol. 66: 1410-1414,
2009.

24. Rotstein, M.; Doran, J.; Yang, H.; Ullner, P. M.; Engelstad, K.;
De Vivo, D. C.: GLUT1 deficiency and alternating hemiplegia of childhood. Neurology 73:
2042-2044, 2009.

25. Rotstein, M.; Engelstad, K.; Yang, H.; Wang, D.; Levy, B.; Chung,
W. K.; De Vivo, D. C.: Glut1 deficiency: inheritance pattern determined
by haploinsufficiency. Ann. Neurol. 68: 955-958, 2010.

26. Sarkar, H. K.; Thorens, B.; Lodish, H. F.; Kaback, H. R.: Expression
of the human erythrocyte glucose transporter in Escherichia coli. Proc.
Nat. Acad. Sci. 85: 5463-5467, 1988.

27. Schneider, S. A.; Paisan-Ruiz, C.; Garcia-Gorostiaga, I.; Quinn,
N. P.; Weber, Y. G.; Lerche, H.; Hardy, J.; Bhatia, K. P.: GLUT1
gene mutations cause sporadic paroxysmal exercise-induced dyskinesias. Mov.
Disord. 24: 1684-1696, 2009.

28. Seidner, G.; Alvarez, M. G.; Yeh, J.-I.; O'Driscoll, K. R.; Klepper,
J.; Stump, T. S.; Wang, D.; Spinner, N. B.; Birnbaum, M. J.; De Vivo,
D. C.: GLUT-1 deficiency syndrome caused by haploinsufficiency of
the blood-brain barrier hexose carrier. Nature Genet. 18: 188-191,
1998.

29. Shepherd, P. R.; Kahn, B. B.: Glucose transporters and insulin
action: implications for insulin resistance and diabetes mellitus. New
Eng. J. Med. 341: 248-257, 1999.

30. Shows, T. B.; Eddy, R. L.; Byers, M. G.; Fukushima, Y.; Dehaven,
C. R.; Murray, J. C.; Bell, G. I.: Polymorphic human glucose transporter
gene (GLUT) is on chromosome 1p31.3-p35. Diabetes 36: 546-549, 1987.

31. Striano, P.; Weber, Y. G.; Toliat, M. R.; Schubert, J.; Leu, C.;
Chaimana, R.; Baulac, S.; Guerrero, R.; LeGuern, E.; Lehesjoki, A.-E.;
Polvi, A.; Robbiano, A.; Serratosa, J. M.; Guerrini, R.; Nurnberg,
P.; Sander, T.; Zara, F.; Lerche, H.; Marini, C.: GLUT1 mutations
are a rare cause of familial idiopathic generalized epilepsy. Neurology 78:
557-562, 2012.

32. Suls, A.; Dedeken, P.; Goffin, K.; Van Esch, H.; Dupont, P.; Cassiman,
D.; Kempfle, J.; Wuttke, T. V.; Weber, Y.; Lerche, H.; Afawi, Z.;
Vandenberghe, W.; and 15 others: Paroxysmal exercise-induced dyskinesia
and epilepsy is due to mutations in SLC2A1, encoding the glucose transporter
GLUT1. Brain 131: 1831-1844, 2008.

33. Suls, A.; Mullen, S. A.; Weber, Y. G.; Verhaert, K.; Ceulemans,
B.; Guerrini, R.; Wuttke, T. V.; Salvo-Vargas, A.; Deprez, L.; Claes,
L. R. F.; Jordanova, A.; Berkovic, S. F.; Lerche, H.; De Jonghe, P.;
Scheffer, I. E.: Early-onset absence epilepsy caused by mutations
in the glucose transporter GLUT1. Ann. Neurol. 66: 415-419, 2009.

34. Wang, D.; Kranz-Eble, P.; De Vivo, D. C.: Mutational analysis
of GLUT1 (SLC2A1) in Glut-1 deficiency syndrome. Hum. Mutat. 16:
224-231, 2000. Note: Erratum: Hum. Mutat. 16: 527 only, 2000.

35. Wang, D.; Pascual, J. M.; Yang, H.; Engelstad, K.; Jhung, S.;
Sun, R. P.; De Vivo, D. C.: Glut-1 deficiency syndrome: clinical,
genetic, and therapeutic aspects. Ann. Neurol. 57: 111-118, 2005.

36. Wang, D.; Pascual, J. M.; Yang, H.; Engelstad, K.; Mao, X.; Cheng,
J.; Yoo, J.; Noebels, J. L.; De Vivo, D. C.: A mouse model for Glut-1
haploinsufficiency. Hum. Molec. Genet. 15: 1169-1179, 2006.

37. Weber, Y. G.; Kamm, C.; Suls, A.; Kempfle, J.; Kotschet, K.; Schule,
R.; Wuttke, T. V.; Maljevic, S.; Liebrich, J.; Gasser, T.; Ludolph,
A. C.; Van Paesschen, W.; Schols, L.; De Jonghe, P.; Auburger, G.;
Lerche, H.: Paroxysmal choreoathetosis/spasticity (DYT9) is caused
by a GLUT1 defect. Neurology 77: 959-964, 2011.

38. Weber, Y. G.; Storch, A.; Wuttke, T. V.; Brockmann, K.; Kempfle,
J.; Maljevic, S.; Margari, L.; Kamm, C.; Schneider, S. A.; Huber,
S. M.; Pekrun, A.; Roebling, R.; and 17 others: GLUT1 mutations
are a cause of paroxysmal exertion-induced dyskinesias and induce
hemolytic anemia by a cation leak. J. Clin. Invest. 118: 2157-2168,
2008.

39. Xiang, K.; Cox, N. J.; Karam, J. H.; Bell, G. I.: Bgl II RFLP
at the human erythrocyte/HepG2-type glucose transporter (GLUT) locus
on chromosome 1. Nucleic Acids Res. 15: 9101 only, 1987.

40. Yun, J.; Rago, C.; Cheong, I.; Pagliarini, R.; Angenendt, P.;
Rajagopalan, H.; Schmidt, K.; Willson, J. K. V.; Markowitz, S.; Zhou,
S.; Diaz, L. A., Jr.; Velculescu, V. E.; Lengauer, C.; Kinzler, K.
W.; Vogelstein, B.; Papadopoulos, N.: Glucose deprivation contributes
to the development of KRAS pathway mutations in tumor cells. Science 325:
1555-1559, 2009.

41. Zheng, P.-P.; Romme, E.; van der Spek, P. J.; Dirven, C. M. F.;
Willemsen, R.; Kros, J. M.: Glut1/SLC2A1 is crucial for the development
of the blood-brain barrier in vivo. Ann. Neurol. 68: 835-844, 2010.

42. Zorzi, G.; Castellotti, B.; Zibordi, F.; Gellera, C.; Nardocci,
N.: Paroxysmal movement disorders in GLUT1 deficiency syndrome. Neurology 71:
146-148, 2008.

*FIELD* CN
Cassandra L. Kniffin - updated: 1/8/2014
Cassandra L. Kniffin - updated: 10/18/2012
Cassandra L. Kniffin - updated: 10/4/2012
Cassandra L. Kniffin - updated: 4/11/2011
Cassandra L. Kniffin - updated: 3/16/2011
Cassandra L. Kniffin - updated: 2/23/2011
Ada Hamosh - updated: 10/13/2009
Patricia A. Hartz - updated: 9/17/2009
Cassandra L. Kniffin - updated: 6/25/2008
Patricia A. Hartz - updated: 5/29/2008
Cassandra L. Kniffin - updated: 5/3/2005
Stylianos E. Antonarakis - updated: 9/2/2004
Cassandra L. Kniffin - updated: 8/16/2004
Natalie E. Krasikov - updated: 3/5/2004
Ada Hamosh - updated: 9/18/2003
Victor A. McKusick - updated: 1/30/2003
Cassandra L. Kniffin - reorganized: 3/22/2002
Victor A. McKusick - updated: 12/5/2001
George E. Tiller - updated: 3/16/2001
John A. Phillips, III - updated: 8/9/2000
Victor A. McKusick - updated: 9/15/1999
Victor A. McKusick - updated: 1/26/1998
Victor A. McKusick - updated: 1/15/1998

*FIELD* CD
Victor A. McKusick: 8/28/1987

*FIELD* ED
carol: 01/17/2014
ckniffin: 1/8/2014
carol: 10/22/2012
ckniffin: 10/18/2012
carol: 10/9/2012
ckniffin: 10/4/2012
carol: 10/3/2012
wwang: 4/14/2011
ckniffin: 4/11/2011
wwang: 4/1/2011
ckniffin: 3/16/2011
carol: 3/15/2011
wwang: 3/8/2011
ckniffin: 2/23/2011
wwang: 2/17/2011
ckniffin: 1/24/2011
terry: 1/12/2011
carol: 11/4/2010
carol: 7/1/2010
ckniffin: 6/30/2010
alopez: 10/23/2009
terry: 10/13/2009
mgross: 9/17/2009
terry: 1/14/2009
wwang: 11/25/2008
ckniffin: 11/17/2008
carol: 8/22/2008
ckniffin: 6/25/2008
mgross: 6/2/2008
terry: 5/29/2008
carol: 2/16/2006
carol: 5/31/2005
ckniffin: 5/3/2005
mgross: 9/2/2004
tkritzer: 8/18/2004
ckniffin: 8/16/2004
carol: 3/5/2004
alopez: 9/18/2003
alopez: 1/31/2003
terry: 1/30/2003
carol: 3/25/2002
carol: 3/22/2002
ckniffin: 3/22/2002
carol: 3/8/2002
terry: 3/8/2002
alopez: 12/7/2001
terry: 12/5/2001
cwells: 5/11/2001
cwells: 3/20/2001
cwells: 3/16/2001
cwells: 3/14/2001
mcapotos: 10/6/2000
joanna: 10/6/2000
mgross: 8/9/2000
carol: 9/30/1999
carol: 9/29/1999
jlewis: 9/28/1999
terry: 9/15/1999
dkim: 7/21/1998
dholmes: 2/20/1998
mark: 1/26/1998
terry: 1/26/1998
mark: 1/19/1998
terry: 1/15/1998
alopez: 12/2/1997
mark: 2/23/1997
carol: 6/4/1992
carol: 6/3/1992
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/27/1989
root: 11/23/1988

MIM 601042
*RECORD*
*FIELD* NO
601042
*FIELD* TI
#601042 DYSTONIA 9; DYT9
;;CHOREOATHETOSIS/SPASTICITY, EPISODIC;;
CSE CHOREOATHETOSIS, PAROXYSMAL, WITH EPISODIC ATAXIA;;
read moreCHOREOATHETOSIS, KINESIGENIC, WITH EPISODIC ATAXIA AND SPASTICITY
*FIELD* TX
A number sign (#) is used with this entry because dystonia-9 (DYT9) is
caused by heterozygous mutation in the SLC2A1 gene (138140), also
referred to as GLUT1, on chromosome 1p34.

Allelic disorders with overlapping features include GLUT1 deficiency
syndrome-1 (GLUT1DS1; 606777), GLUT1DS2 (612126), and idiopathic
generalized epilepsy-12 (EIG12; 614847).

DESCRIPTION

Dystonia-9 is an autosomal dominant neurologic disorder characterized by
childhood onset of paroxysmal choreoathetosis and progressive spastic
paraplegia. Most show some degree of cognitive impairment. Other
variable features may include seizures, migraine headaches, and ataxia
(summary by Weber et al., 2011).

CLINICAL FEATURES

Auburger et al. (1996) described a large German pedigree with autosomal
dominant paroxysmal choreoathetosis and spasticity. A total of 18
affected and 11 unaffected family members were clinically evaluated. Age
of onset ranged from 2 to 15 years, with most individuals presenting
clear symptoms before attending school. Patients complained of episodes
of involuntary movements, dystonic posture of toes, legs, and arms,
imbalance, dysarthria, paresthesias periorally and on the lower limbs,
and double vision, sometimes accompanied or followed by headache.
Cerebellar ataxia was not seen in the episodes observed. The episodes
lasted approximately 20 minutes, and occurred at frequencies ranging
from twice a day to twice a year. Physical exercise, emotional stress,
lack of sleep, and alcohol consumption were mentioned as precipitating
factors. While physical examination was usually normal in the clinical
interval, 5 patients exhibited constant spastic paraplegia as evidenced
by spastic leg tone, increased tendon reflexes, and pyramidal signs in
the lower limbs, without increased latencies on motor evoked potential
analysis. Affected individuals were described as good natured and simple
minded; 1 patient was 'analphabetic.'

Weber et al. (2011) reported Australian adult monozygotic twin brothers
with DYT9 and mental retardation. They presented with paroxysmal
choreoathetosis and progressive spastic paraparesis; ataxia was not
observed. As toddlers, they both developed episodic stereotyped,
abnormal movements mainly affecting the limbs. The movements progressed
to vigorous choreatic movements without impairment of consciousness.
Episodes lasted between 5 minutes and 2 hours, and occurred several
times weekly. Precipitating factors included prolonged exercise or
physical exhaustion, dehydration, caffeine, alcohol, and anticipation of
food. Medication was not beneficial for these episodes. In addition,
both had a persistent gait disturbance due to progressive spastic
paraparesis since later childhood, with markedly increased tone,
sustained clonus, pyramidal pattern weakness, brisk reflexes, and
extensor plantar responses.

INHERITANCE

The transmission pattern in the family with paroxysmal choreoathetosis
reported by Auburger et al. (1996) was consistent with autosomal
dominant inheritance.

CLINICAL MANAGEMENT

Bain et al. (1992) demonstrated a rise in pH in the cerebellum with
(31)P nuclear magnetic resonance spectroscopy in 6 affected members of 2
unrelated families with familial periodic cerebellar ataxia consistent
with ataxia (see 108500). Consistent with this finding, acetazolamide
stopped or alleviated symptoms. In contrast, Auburger et al. (1996)
found no clear elevation of pH in their family. They stated, however,
that episodes ceased in one patient after administration of
acetazolamide and phenytoin and were ameliorated in a second patient by
acetazolamide but continued in a third patient despite treatment with a
range of agents.

MAPPING

By linkage analysis in a large pedigree with paroxysmal choreoathetosis
with episodic ataxia and spasticity, Auburger et al. (1996) concluded
that the gene for this disorder probably lies in a 2-cM region between
D1S443 and D1S197. They noted that a cluster of potassium channel genes
is located on 1p.

MOLECULAR GENETICS

In affected members of the family with DYT9 originally reported by
Auburger et al. (1996), Weber et al. (2011) identified a heterozygous
mutation in the SLC2A1 gene (R232C; 138140.0018). Two Australian
brothers with the disorder carried a different heterozygous mutation
(R126C; 138140.0014).

NOMENCLATURE

Muller et al. (1998) referred to this disorder as dystonia-9 and
suggested that it is closely related to paroxysmal dystonic
choreoathetosis (PDC; 118800), which they referred to as dystonia-8. The
involuntary movements and dystonia in DYT9 are similar to those in PDC,
which maps to chromosome 2. In both disorders, episodes can be induced
by alcohol, fatigue, and emotional stress; however, in DYT9, physical
exercise can precipitate the episodes, and 5 of the 18 patients studied
by Auburger et al. (1996) had spastic paraplegia both during and between
episodes of dyskinesia.

*FIELD* RF
1. Auburger, G.; Ratzlaff, T.; Lunkes, A.; Nelles, H. W.; Leube, B.;
Binkofski, F.; Kugel, H.; Heindel, W.; Seitz, R.; Benecke, R.; Witte,
O. W.; Voit, T.: A gene for autosomal dominant paroxysmal choreoathetosis/spasticity
(CSE) maps to the vicinity of a potassium channel gene cluster on
chromosome 1p, probably within 2 cM between D1S443 and D1S197. Genomics 31:
90-94, 1996.

2. Bain, P. G.; O'Brien, M. D.; Keevil, S. F.; Porter, D. A.: Familial
periodic cerebellar ataxia: a problem of cerebellar intracellular
pH homeostasis. Ann. Neurol. 31: 147-154, 1992.

3. Muller, U.; Steinberger, D.; Nemeth, A. H.: Clinical and molecular
genetics of primary dystonias. Neurogenetics 1: 165-177, 1998.

4. Weber, Y. G.; Kamm, C.; Suls, A.; Kempfle, J.; Kotschet, K.; Schule,
R.; Wuttke, T. V.; Maljevic, S.; Liebrich, J.; Gasser, T.; Ludolph,
A. C.; Van Paesschen, W.; Schols, L.; De Jonghe, P.; Auburger, G.;
Lerche, H.: Paroxysmal choreoathetosis/spasticity (DYT9) is caused
by a GLUT1 defect. Neurology 77: 959-964, 2011.

*FIELD* CS
INHERITANCE:
Autosomal dominant

HEAD AND NECK:
[Eyes];
Diplopia

NEUROLOGIC:
[Central nervous system];
Ataxia, episodic;
Spasticity;
Dysarthria;
Dystonia;
Involuntary movements;
Dyskinesias;
Choreoathetosis;
Spastic paraplegia;
Hyperreflexia;
Pyramidal signs;
Tonic-clonic seizures (less common);
Migraine;
Headache;
Cognitive impairment;
[Peripheral nervous system];
Paresthesias

MISCELLANEOUS:
Onset at 2 to 15 years;
Symptoms precipitated by stress, exertion, fatigue, alcohol;
Variable features;
Some patients respond to acetazolamide

MOLECULAR BASIS:
Caused by mutation in the solute carrier family 2 (facilitated glucose
transporter), member 1 gene (SLC2A1, 138140.0018)

*FIELD* CN
Cassandra L. Kniffin - updated: 10/4/2012
Cassandra L. Kniffin - revised: 8/14/2002

*FIELD* CD
John F. Jackson: 6/15/1995

*FIELD* ED
joanna: 10/25/2012
ckniffin: 10/4/2012
ckniffin: 8/14/2002

*FIELD* CN
Cassandra L. Kniffin - updated: 10/4/2012
Victor A. McKusick - updated: 5/5/1998
Orest Hurko - updated: 4/1/1996

*FIELD* CD
Victor A. McKusick: 2/6/1996

*FIELD* ED
joanna: 05/10/2013
carol: 10/9/2012
ckniffin: 10/4/2012
alopez: 4/6/2010
joanna: 3/18/2004
carol: 5/22/1998
carol: 5/16/1998
carol: 5/13/1998
terry: 5/5/1998
terry: 11/11/1997
alopez: 6/11/1997
mark: 12/20/1996
jamie: 12/18/1996
mark: 12/11/1996
mark: 6/19/1996
terry: 4/15/1996
terry: 4/1/1996
terry: 3/22/1996
mark: 2/7/1996

MIM 606777
*RECORD*
*FIELD* NO
606777
*FIELD* TI
#606777 GLUT1 DEFICIENCY SYNDROME 1; GLUT1DS1
;;GLUCOSE TRANSPORT DEFECT, BLOOD-BRAIN BARRIER
read moreGLUT1 DEFICIENCY SYNDROME 1, AUTOSOMAL RECESSIVE, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because GLUT1 deficiency
syndrome-1 (GLUT1DS1) is caused by heterozygous mutation in the gene
encoding the GLUT1 transporter (SLC2A1; 138140) on chromosome
1p35-p31.3. Rare cases of GLUT1 deficiency caused by homozygous or
compound heterozygous mutation in the SLC2A1 gene have been reported.

Allelic disorders with overlapping features include GLUT1 deficiency
syndrome-2 (GLUT1DS2; 612126), dystonia-9 (DYT9; 601042), and idiopathic
generalized epilepsy-12 (EIG12; 614847).

DESCRIPTION

GLUT1 deficiency syndrome-1 is a neurologic disorder showing wide
phenotypic variability. The most severe 'classic' phenotype comprises
infantile-onset epileptic encephalopathy associated with delayed
development, acquired microcephaly, motor incoordination, and
spasticity. Onset of seizures, usually characterized by apneic episodes,
staring spells, and episodic eye movements, occurs within the first 4
months of life. Other paroxysmal findings include intermittent ataxia,
confusion, lethargy, sleep disturbance, and headache. Varying degrees of
cognitive impairment can occur, ranging from learning disabilities to
severe mental retardation. Hypoglycorrhachia (low CSF glucose, less than
40 mg/dl) and low CSF lactate are essentially diagnostic for the
disorder. As more cases with GLUT1 deficiency syndrome are described,
the phenotype has broadened to include individuals with ataxia and
mental retardation but without seizures, individuals with dystonia and
choreoathetosis, and rare individuals with absence seizures and no
movement disorder. The disorder, which results from a defect in the
GLUT1 glucose transporter causing decreased glucose concentration in the
central nervous system, is part of a spectrum of neurologic phenotypes
resulting from GLUT1 deficiency. GLUT deficiency syndrome-2 (612126)
represents the less severe end of the phenotypic spectrum and is
associated with paroxysmal exercise-induced dystonia with or without
seizures. Correct diagnosis of GLUT1 deficiency is important because a
ketogenic diet often results in marked clinical improvement of the motor
and seizure symptoms (reviews by Pascual et al., 2004 and Brockmann,
2009).

CLINICAL FEATURES

De Vivo et al. (1991) described 2 patients with infantile seizures,
delayed development, and acquired microcephaly who had normal
circulating blood sugar, low to normal cerebrospinal fluid lactate, but
persistent hypoglycorrhachia and diminished transport of hexose into
isolated red blood cells. These symptoms suggested the existence of a
defect in glucose transport across the blood-brain barrier.

Wang et al. (2000) used the designation GLUT1 deficiency syndrome for
the disorder observed in 15 children who presented with infantile
seizures, acquired microcephaly, and developmental delay and were found
to have heterozygous mutations in the GLUT1 gene. The deficiency in the
transporter resulted in reduced cerebrospinal fluid glucose
concentrations and reduced erythrocyte glucose transporter activities in
the patients. Rotstein et al. (2010) provided further details of a
patient with autosomal recessive GLUT1 deficiency syndrome reported by
Wang et al. (2000). He developed recurrent limb stiffening and cyanosis
at age 6 weeks. Seizures included tonic eye deviation, staring spells,
myoclonic jerks, and prolonged and refractory generalized tonic-clonic
seizures. He had delayed psychomotor development and progressive
microcephaly. CSF showed hypoglycorrhachia. A ketogenic diet was helpful
with seizure control, but at age 6 years, his developmental quotient was
42. He had axial hypotonia, limb spasticity and dystonia, and severe
ataxia.

Brockmann et al. (2001) reported a family in which GLUT1 deficiency
presented in certain members with mild to severe seizures, developmental
delay, ataxia, hypoglycorrhachia, and decreased erythrocyte uptake of
3-O-methyl-D-glucose. Seizure frequency and severity were aggravated by
fasting, and responded to a carbohydrate load. Ultimately, however, the
seizures and motor disability in the patients responded best to a
ketogenic diet (Brockmann, 2009).

Klepper and Voit (2002) provided a detailed review of GLUT1 deficiency,
including clinical features, a diagnostic algorithm, and effective
treatment strategies.

Wang et al. (2005) found that 13 (81%) of 16 patients with GLUT1
deficiency syndrome-1 had the most common 'classic' phenotype, a
developmental encephalopathy with infantile seizures, acquired
microcephaly, and spasticity. Seizure type varied and included
generalized tonic or clonic, myoclonic, atypical absence, atonic, and
unclassified. Seizures were unresponsive to typical anticonvulsant
medication, but responded rapidly to a ketogenic diet. Patients with the
classic phenotype also experienced other variable paroxysmal events,
including confusion, lethargy, hemiparesis, ataxia, sleep disturbances,
and headaches. Cognitive impairment ranged from learning disabilities to
severe mental retardation; some patients had impaired speech and
language development. Neurologic signs showed variable involvement of
the pyramidal, extrapyramidal, and cerebellar systems.

Zorzi et al. (2008) reported 3 unrelated Italian females with GLUT1
deficiency associated with paroxysmal movement disorders diagnosed in
early adulthood. None had a positive family history. All had global
developmental delay noted in infancy, and 2 had seizures beginning in
the first 6 months of life (myoclonic absence and complex partial
seizures, respectively). All had microcephaly, dysarthria, spasticity,
and moderate mental retardation. Paroxysmal movements included myoclonic
jerks, stiffening, and dystonic posturing. The phenotype in the 2
patients with early-onset seizures was consistent with GLUT1DS1; the
other patient did not have seziures, but had ataxia, spasticity,
dystonia, and dysarthria, more similar to the phenotype observed in
GLUT1 syndrome-2 (612126). Genetic analysis identified a different
heterozygous mutation in the GLUT1 gene in each patient (see, e.g.,
138140.0014). Zorzi et al. (2008) noted that the abnormal movements were
consistent with paroxysmal dyskinesia, thus expanding the phenotype
associated with GLUT1 deficiency.

- Clinical Variability

Mullen et al. (2011) found that 4 (5%) of 84 probands with myoclonic
astatic epilepsy (MAE) had a mutation in the SLC2A1 gene, consistent
with GLUT1 deficiency. Three of the patients fulfilled the narrow
definition of MAE, and 1 fit a broader definition. The first 3 patients
had onset of multiple seizure types, including myoclonic-atonic
seizures, by age 3 years, and subsequent cognitive decline, resulting in
severe intellectual disability in patients 1 and 3. Patient 2, who was
treated early with a ketogenic diet, had mild intellectual disability.
The patient with the broader definition of MAE had onset at age 4 years
of atonic and absence seizures, followed by a progressive epileptic
encephalopathy and mild intellectual disability. Two of the patients
also developed paroxysmal exertional dyskinesia in childhood. The
findings were important because GLUT1 deficient patients can be treated
with a ketogenic diet. Mullen et al. (2011) suggested that patients with
MAE should be tested for GLUT1 deficiency.

DIAGNOSIS

Yang et al. (2011) performed an erythrocyte glucose uptake assay in 109
patients with suspected GLUT1 deficiency. There were 2 groups of
patients: 74 had decreased glucose uptake (mean of about 55% compared to
controls) and 35 had normal uptake. The ROC curve defined a new cutoff
of 74%, which was increased from the previously accepted cutoff of 60%.
The 74% cutoff increased the specificity and sensitivity of the assay to
100% and 99%, respectively. Pathogenic SLC2A1 mutations were found in
95% of patients with decreased uptake and in only 1 patient with normal
uptake. Among those with defects, there was a significant inverse
correlation between median values of uptake and clinical severity. The
findings validated the erythrocyte glucose uptake assay as a
confirmatory functional test for GLUT1 deficiency and as a surrogate
marker for GLUT1 haploinsufficiency.

- Diagnostic Criteria

In a review, Klepper and Leiendecker (2007) proposed diagnostic criteria
for GLUT1 deficiency syndrome: seizures, developmental delay, complex
movement disorder, and fasting EEG changes that improve postprandially.
Laboratory criteria for the disorder include hypoglycorrhachia, low
CSF/blood glucose ratio, low to normal CSF lactate, and reduced
erythrocyte glucose uptake and/or decreased GLUT1 immunoreactivity in
erythrocyte membranes.

PATHOGENESIS

Pascual et al. (2007) compared the clinical phenotype of 2 unrelated
patients with neuroglycopenia in infancy: a 16-year-old boy who had
GLUT1 deficiency confirmed by genetic analysis and a 23-year-old woman
who had early infantile chronic hypoglycemia due to hyperinsulinism and
pancreatic nesidioblastosis (see, e.g., 256450). The woman had an
unaffected twin sister who served as a control. Both patients had
residual encephalopathy with hypertonicity, dysarthria, hyperreflexia,
ataxia, mental retardation, and microcephaly. Neuropsychologic testing
revealed decreased IQ, articulation difficulties, and friendly demeanor
in both patients. Pascual et al. (2007) concluded that a persistent
decrease in glucose in the developing brain is the unifying pathogenic
mechanism in both of these disorders, which can be classified as
infantile neuroglycopenia. The authors hypothesized that glucose serves
a dual capacity in the developing brain, acting both as a fuel and as a
signaling molecule.

INHERITANCE

Klepper et al. (2001) reported a father and 2 children from separate
marriages who were affected by GLUT1 deficiency, and confirmed autosomal
dominant transmission by identifying a heterozygous mutation in the
GLUT1 gene (G91D; 138140.0006).

In the family reported by Brockmann et al. (2001), the GLUT1 deficiency
syndrome affected 5 members over 3 generations. The syndrome behaved as
an autosomal dominant, with 1 instance of father-to-son transmission.

Rare cases of autosomal recessive transmission have been reported (Wang
et al., 2000; Klepper et al., 2009). The patient reported by Klepper et
al. (2009) was a 6-year-old girl born to consanguineous Arab parents
from a Bedouin kindred from Qatar. She was noted to have unsteady ataxic
gait at age 18 months, as well as paroxysmal choreoathetosis. She also
had developmental delay and hypotonia. EEG showed a polymorphic baseline
alpha-theta activity with an isolated monomorphic sharp wave focus.
Lumbar puncture showed hypoglycorrhachia and decreased CSF lactate.
Genetic analysis identified a homozygous mutation in the GLUT1 gene
(R468W; 138140.0016). Her asymptomatic 2-year-old sister was also
homozygous for the mutation; she was found to have hypoglycorrhachia and
decreased CSF lactate. The parents, who were unaffected, were
heterozygous for the mutation. Klepper et al. (2009) concluded that the
mutation was pathogenic, and suggested that the sister who was
homozygous for the mutation was too young for symptom onset. The
findings suggested that GLUT1 deficiency can also be inherited in an
autosomal recessive pattern.

CLINICAL MANAGEMENT

Klepper et al. (2002) used the ketogenic diet to treat 4 patients with
seizures and low CSF glucose suggesting GLUT1 deficiency, which was
confirmed in 2 of the patients. All 4 were started on a ketogenic diet
at 6 to 28 weeks of age. Ketosis developed within 24 hours.
3-Hydroxybutyrate concentrations available at the bedside correlated
inversely with the base excess. At glucose levels of 40 mg/dl or less,
patients remained asymptomatic in the presence of ketones. The ketogenic
formula was tolerated well, parental compliance was good, and all
patients remained seizure-free on the diet. One infant developed failure
to thrive on medium-chain triglycerides, which was reversed using
long-chain triglycerides. Adverse effects of the diet were limited to
renal stones in 1 patient. Klepper et al. (2002) concluded that seizure
control was effective and adverse effects were limited, but that
evaluation of long-term effects was necessary.

Klepper et al. (2003) reported in vitro studies of the effects of
preincubation of anticonvulsants and ethanol on GLUT1-mediated glucose
transport in erythrocytes from 11 patients and 30 controls. They
concluded that ethanol, diazepam, chloralhydrate, phenobarbital, and
pentobarbital could exacerbate the effect of GLUT1 deficiency on glucose
transport into the brain, whereas phenytoin and carbamazepine had no
significant inhibitory effects and might be preferable for use in
seizure control. They noted that recommendations should be viewed with
caution as the data did not assess cerebral glucose utilization.

Wang et al. (2005) reported that the ketogenic diet effectively
controlled seizures and other motor symptoms of GLUT1 deficiency, but
was less effective on cognitive symptoms.

Klepper et al. (2005) reported favorable seizure control with a
ketogenic diet in 15 patients with GLUT1 deficiency. Two patients had
recurrence of seizures after 2.5 years despite adequate ketosis, but
were controlled by other medications.

MOLECULAR GENETICS

Seidner et al. (1998) demonstrated 2 classes of mutations as the
molecular basis for the functional defect of glucose transport:
hemizygosity of GLUT1 (138140.0001) and heterozygous nonsense mutations
resulting in truncation of the GLUT1 protein (e.g., 138140.0002).

Abnormalities in the GLUT1 gene found by Wang et al. (2000) included 1
large deletion (138140.0001), 5 missense mutations (see, e.g.,
138140.0004-138140.0005), 3 small deletions, 3 insertions, 3 splice site
mutations, and 1 nonsense mutation. In the family with GLUT1 deficiency
syndrome-1 reported by Brockmann et al. (2001), a heterozygous
arg126-to-his missense mutation in the GLUT1 gene was identified
(138140.0007).

ANIMAL MODEL

Wang et al. (2006) found that mice with targeted heterozygous disruption
of the Glut1 gene developed spontaneous epileptiform discharges,
impaired motor activity, incoordination, hypoglycorrhachia, decreased
brain weight (microencephaly), decreased brain glucose uptake, and
decreased expression of Glut1 in the brain (66% of controls). Homozygous
mutant mice were embryonic lethal. Wang et al. (2006) suggested that
Glut1 +/- mice mimics the classic human presentation of GLUT1 deficiency
and can be used as an animal model to examine the pathophysiology of the
disorder in vivo.

*FIELD* SA
Suls et al. (2009)
*FIELD* RF
1. Brockmann, K.: The expanding phenotype of GLUT1-deficiency syndrome. Brain
Dev. 31: 545-552, 2009.

2. Brockmann, K.; Wang, D.; Korenke, C. G.; von Moers, A.; Ho, Y.-Y.;
Pascual, J. M.; Kuang, K.; Yang, H.; Ma, L.; Kranz-Eble, P.; Fischbarg,
J.; Hanefeld, F.; De Vivo, D. C.: Autosomal dominant Glut-1 deficiency
syndrome and familial epilepsy. Ann. Neurol. 50: 476-485, 2001.

3. De Vivo, D. C.; Trifiletti, R. R.; Jacobson, R. I.; Ronen, G. M.;
Behmand, R. A.; Harik, S. I.: Defective glucose transport across
the blood-brain barrier as a cause of persistent hypoglycorrhachia,
seizures, and developmental delay. New Eng. J. Med. 325: 703-709,
1991.

4. Klepper, J.; Florcken, A.; Fischbarg, J.; Voit, T.: Effects of
anticonvulsants on GLUT1-mediated glucose transport in GLUT1 deficiency
syndrome in vitro. Europ. J. Pediat. 162: 84-89, 2003.

5. Klepper, J.; Leiendecker, B.: GLUT1 deficiency syndrome-2007 update. Dev.
Med. Child Neurol. 49: 707-716, 2007.

6. Klepper, J.; Leiendecker, B.; Bredahl, R.; Athanassopoulos, S.;
Heinen, F.; Gertsen, E.; Florcken, A.; Metz, A.; Voit, T.: Introduction
of a ketogenic diet in young infants. J. Inherit. Metab. Dis. 25:
449-460, 2002.

7. Klepper, J.; Scheffer, H.; Elsaid, M. F.; Kamsteeg, E.-J.; Leferink,
M.; Ben-Omran, T.: Autosomal recessive inheritance of GLUT1 deficiency
syndrome. Neuropediatrics 40: 207-210, 2009.

8. Klepper, J.; Scheffer, H.; Leiendecker, B.; Gertsen, E.; Binder,
S.; Leferink, M.; Hertzberg, C.; Nake, A.; Voit, T.; Willemsen, M.
A.: Seizure control and acceptance of the ketogenic diet in GLUT1
deficiency syndrome: a 2- to 5-year follow-up of 15 children enrolled
prospectively. Neuropediatrics 36: 302-308, 2005.

9. Klepper, J.; Voit, T.: Facilitated glucose transporter protein
type 1 (GLUT1) deficiency syndrome: impaired glucose transport into
brain--a review. Europ. J. Pediat. 161: 295-304, 2002.

10. Klepper, J.; Willemsen, M.; Verrips, A.; Guertsen, E.; Herrmann,
R.; Kutzick, C.; Florcken, A.; Voit, T.: Autosomal dominant transmission
of GLUT1 deficiency. Hum. Molec. Genet. 10: 63-68, 2001.

11. Mullen, S. A.; Marini, C.; Suls, A.; Mei, D.; Della Giustina,
E.; Buti, D.; Arsov, T.; Damiano, J.; Lawrence, K.; De Jonghe, P.;
Berkovic, S. F.; Scheffer, I. E.; Guerrini, R.: Glucose transporter
1 deficiency as a treatable cause of myoclonic astatic epilepsy. Arch.
Neurol. 68: 1152-1155, 2011.

12. Pascual, J. M.; Wang, D.; Hinton, V.; Engelstad, K.; Saxena, C.
M.; Van Heertum, R. L.; De Vivo, D. C.: Brain glucose supply and
the syndrome of infantile neuroglycopenia. Arch. Neurol. 64: 507-513,
2007.

13. Pascual, J. M.; Wang, D.; Lecumberri, B.; Yang, H.; Mao, X.; Yang,
R.; De Vivo, D. C.: GLUT1 deficiency and other glucose transporter
diseases. Europ. J. Endocr. 150: 627-633, 2004.

14. Rotstein, M.; Engelstad, K.; Yang, H.; Wang, D.; Levy, B.; Chung,
W. K.; De Vivo, D. C.: Glut1 deficiency: inheritance pattern determined
by haploinsufficiency. Ann. Neurol. 68: 955-958, 2010.

15. Seidner, G.; Alvarez, M. G.; Yeh, J.-I.; O'Driscoll, K. R.; Klepper,
J.; Stump, T. S.; Wang, D.; Spinner, N. B.; Birnbaum, M. J.; De Vivo,
D. C.: GLUT-1 deficiency syndrome caused by haploinsufficiency of
the blood-brain barrier hexose carrier. Nature Genet. 18: 188-191,
1998.

16. Suls, A.; Mullen, S. A.; Weber, Y. G.; Verhaert, K.; Ceulemans,
B.; Guerrini, R.; Wuttke, T. V.; Salvo-Vargas, A.; Deprez, L.; Claes,
L. R. F.; Jordanova, A.; Berkovic, S. F.; Lerche, H.; De Jonghe, P.;
Scheffer, I. E.: Early-onset absence epilepsy caused by mutations
in the glucose transporter GLUT1. Ann. Neurol. 66: 415-419, 2009.

17. Wang, D.; Kranz-Eble, P.; De Vivo, D. C.: Mutational analysis
of GLUT1 (SLC2A1) in Glut-1 deficiency syndrome. Hum. Mutat. 16:
224-231, 2000. Note: Erratum: Hum. Mutat. 16: 527 only, 2000.

18. Wang, D.; Pascual, J. M.; Yang, H.; Engelstad, K.; Jhung, S.;
Sun, R. P.; De Vivo, D. C.: Glut-1 deficiency syndrome: clinical,
genetic, and therapeutic aspects. Ann. Neurol. 57: 111-118, 2005.

19. Wang, D.; Pascual, J. M.; Yang, H.; Engelstad, K.; Mao, X.; Cheng,
J.; Yoo, J.; Noebels, J. L.; De Vivo, D. C.: A mouse model for Glut-1
haploinsufficiency. Hum. Molec. Genet. 15: 1169-1179, 2006.

20. Yang, H.; Wang, D.; Engelstad, K.; Bagay, L.; Wei, Y.; Rotstein,
M.; Aggarwal, V.; Levy, B.; Ma, L.; Chung, W. K.; De Vivo, D. C.:
Glut1 deficiency syndrome and erythrocyte glucose uptake assay. Ann.
Neurol. 70: 996-1005, 2011.

21. Zorzi, G.; Castellotti, B.; Zibordi, F.; Gellera, C.; Nardocci,
N.: Paroxysmal movement disorders in GLUT1 deficiency syndrome. Neurology 71:
146-148, 2008.

*FIELD* CS
INHERITANCE:
Autosomal dominant;
Autosomal recessive (rare)

HEAD AND NECK:
[Head];
Microcephaly, acquired;
Deceleration of head growth;
[Eyes];
Abnormal eye movements, paroxysmal

NEUROLOGIC:
[Central nervous system];
Infantile seizures (approximately 80% of patients);
Seizures, generalized tonic/clonic, myoclonic, atonic, or atypical
absence, aggravated by fatigue and fasting with frequency ranges from
daily to monthly (in some patients);
Myoclonic astatic epilepsy;
Ataxia;
Spasticity;
Increased tone;
Hyperreflexia;
Extensor plantar responses;
Confusion, paroxysmal;
Lethargy, paroxysmal;
Sleep disturbances;
Hemiparesis, paroxysmal;
Total body paralysis, paroxysmal;
Dystonia, paroxysmal;
Myoclonus, paroxysmal;
Dysarthria;
Developmental delay;
Learning disabilities;
Mental retardation;
Speech and language difficulties;
Choreoathetosis (in a subset of patients);
EEG abnormalities

LABORATORY ABNORMALITIES:
Hypoglycorrhachia (low glucose in CSF);
Low-to-normal CSF lactate;
Reduced erythrocyte glucose/hexose transport

MISCELLANEOUS:
Onset in infancy;
Phenotypic variability;
Favorable response to a ketogenic diet;
See also GLUT1DS2 (612126), an allelic disorder with a less severe
phenotype

MOLECULAR BASIS:
Caused by mutation in the solute carrier family 2 (facilitated glucose
transporter), member 1 gene (SLC2A1, 138140.0001)

*FIELD* CN
Cassandra L. Kniffin - updated: 4/4/2012
Cassandra L. Kniffin - updated: 6/30/2010
Cassandra L. Kniffin - updated: 5/3/2005

*FIELD* CD
Cassandra L. Kniffin: 5/8/2002

*FIELD* ED
joanna: 04/25/2012
ckniffin: 4/4/2012
joanna: 10/21/2011
ckniffin: 6/30/2010
joanna: 12/7/2005
ckniffin: 5/3/2005
ckniffin: 5/8/2002

*FIELD* CN
Cassandra L. Kniffin - updated: 10/4/2012
Cassandra L. Kniffin - updated: 4/4/2012
Cassandra L. Kniffin - updated: 1/5/2012
Cassandra L. Kniffin - updated: 4/11/2011
Cassandra L. Kniffin - updated: 3/16/2011
Cassandra L. Kniffin - updated: 1/24/2011
Cassandra L. Kniffin - updated: 6/30/2010
Cassandra L. Kniffin - updated: 10/1/2007
Cassandra L. Kniffin - updated: 6/7/2007
Cassandra L. Kniffin - updated: 5/7/2007
Cassandra L. Kniffin - updated: 5/3/2005

*FIELD* CD
Cassandra L. Kniffin: 3/22/2002

*FIELD* ED
carol: 10/22/2012
ckniffin: 10/22/2012
carol: 10/22/2012
carol: 10/9/2012
ckniffin: 10/4/2012
carol: 4/6/2012
ckniffin: 4/4/2012
carol: 1/5/2012
ckniffin: 1/5/2012
wwang: 4/14/2011
ckniffin: 4/11/2011
wwang: 4/1/2011
ckniffin: 3/16/2011
wwang: 2/17/2011
ckniffin: 1/24/2011
carol: 7/7/2010
carol: 7/1/2010
ckniffin: 6/30/2010
wwang: 11/25/2008
carol: 8/22/2008
ckniffin: 6/25/2008
wwang: 10/4/2007
ckniffin: 10/1/2007
wwang: 6/28/2007
ckniffin: 6/7/2007
wwang: 5/10/2007
ckniffin: 5/7/2007
terry: 6/8/2005
carol: 5/31/2005
ckniffin: 5/3/2005
carol: 7/13/2004
ckniffin: 7/9/2004
carol: 3/25/2002
ckniffin: 3/25/2002
ckniffin: 3/22/2002

MIM 612126
*RECORD*
*FIELD* NO
612126
*FIELD* TI
#612126 GLUT1 DEFICIENCY SYNDROME 2; GLUT1DS2
;;PAROXYSMAL EXERCISE-INDUCED DYSKINESIA WITH OR WITHOUT EPILEPSY AND/OR
read moreHEMOLYTIC ANEMIA;;
PED WITH OR WITHOUT EPILEPSY AND/OR HEMOLYTIC ANEMIA;;
PAROXYSMAL EXERTION-INDUCED DYSTONIA WITH OR WITHOUT EPILEPSY AND/OR
HEMOLYTIC ANEMIA;;
DYSTONIA 18; DYT18
*FIELD* TX
A number sign (#) is used with this entry because GLUT1 deficiency
syndrome-2 (GLUT1DS2), also known as paroxysmal exercise-induced
dyskinesia (PED) with or without epilepsy and/or hemolytic anemia and as
dystonia-18 (DYT18), is caused by heterozygous mutation in the SLC2A1
gene (138140), which encodes the GLUT1 transporter, on chromosome 1p34.

Allelic disorders with overlapping features include GLUT1 deficiency
syndrome-1 (GLUT1DS1; 606777), dystonia-9 (DYT9; 601042), and idiopathic
generalized epilepsy-12 (EIG12; 614847).

DESCRIPTION

GLUT1 deficiency syndrome-2 is an autosomal dominant disorder
characterized primarily by onset in childhood of paroxysmal
exercise-induced dyskinesia. The dyskinesia involves transient abnormal
involuntary movements, such as dystonia and choreoathetosis, induced by
exercise or exertion, and affecting the exercised limbs. Some patients
may also have epilepsy, most commonly childhood absence epilepsy, with
an average onset of about 2 to 3 years. Mild mental retardation may also
occur. One family has been reported with the additional feature of
hemolytic anemia (Weber et al., 2008). GLUT1 deficiency syndrome-2 shows
wide clinical variability both within and between affected families. The
disorder, which results from a defect in the GLUT1 glucose transporter
causing decreased glucose concentration in the central nervous system,
is part of a spectrum of neurologic phenotypes resulting from GLUT1
deficiency. GLUT1 deficiency syndrome-1 (606777) represents the more
severe end of the phenotypic spectrum. Correct diagnosis of GLUT1
deficiency is important because a ketogenic diet often results in marked
clinical improvement in motor and seizure symptoms (reviews by Pascual
et al., 2004 and Brockmann, 2009).

CLINICAL FEATURES

Plant et al. (1984) reported a mother and daughter with exercise-induced
paroxysmal dystonia. The mother first developed involuntary movements of
the legs after walking at age 8 years. Involvement of the upper limbs
sometimes occurred with stress or continuous writing. The attacks could
also be elicited with other stimuli, including passive movement and
vibration. The patient's daughter was similarly affected.

Margari et al. (2000) reported a family in which 6 members had
paroxysmal exertion-induced dyskinesia with onset in childhood. Other
precipitating factors included fasting and stress. The attacks were
characterized by involuntary flexing and extending movements and
alternately twisting movements of the upper and lower limbs lasting
between 10 and 40 minutes. All patients also had absence seizures or
partial complex seizures, which spontaneously resolved with age. One
patient had generalized tonic-clonic seizures. Some had mild learning
disabilities and irritable behavior with aggressive or impulsive
outbursts. The dyskinesias showed decreased frequency with age. Detailed
neurophysiologic studies suggested hyperexcitability at the muscular and
brain cell membrane levels, and Margari et al. (2000) postulated a
defect in an ion channel.

Munchau et al. (2000) reported a family in which 4 members had
paroxysmal exercise-induced dystonia with a mean age at onset of 12
years (range, 9-15 years). Attacks of PED in affected members were
predominantly dystonic and lasted between 15 and 30 minutes. They were
consistently precipitated by walking but could also occur after other
exercise. Three patients also had migraine without aura.

Overweg-Plandsoen et al. (2003) reported a 6-year-old boy with delayed
psychomotor development, moderate mental retardation, horizontal
nystagmus, dysarthria, limb ataxia, hyperreflexia, and dystonic
posturing of the limbs. He had never had seizures. The motor activity
and coordination fluctuated throughout the day, which was unrelated to
food intake. Laboratory studies showed hypoglycorrhachia and low CSF
lactate. Genetic analysis identified a de novo heterozygous mutation in
the GLUT1 gene (N34I; 138140.0011). A ketogenic diet helped with the
motor symptoms.

Wang et al. (2005) reported 3 patients with an atypical phenotype of
GLUT1 deficiency syndrome without infantile seizures. Two had a
phenotype consistent with that reported in a child by Overweg-Plandsoen
et al. (2003): all had mental retardation, dysarthria, dystonia, and
ataxia, but no seizures. The third patient with an atypical phenotype
reported by Wang et al. (2005) had choreoathetosis, dystonia, paroxysmal
episodes of blinking, and abnormal head and eye movements, which ceased
at age 3 years. He also had hypotonia, dysarthria, and developmental
delay. Biochemical analysis showed that all patients had decreased CSF
glucose and decreased glucose uptake into erythrocytes compared to
controls.

Kamm et al. (2007) reported a German family in which 4 individuals
spanning 3 generations had paroxysmal exercise-induced dystonia, 2 of
whom also had clinical seizures. Onset of PED ranged from 2 to 10 years
and affected the legs. One woman had generalized seizures during
pregnancy at age 22 years, and a boy had onset of frequent absence
seizures at age 3.5 years. EEG studies showed abnormalities in all 4
patients, even those without seizures, as well as in 2 unaffected family
members. EEG findings were variable, and included synchronous and
hypersynchronous spike-wave complexes, sharp waves, and rhythmic theta-
and delta-activity. Two individuals had speech and developmental delay,
and 1 had migraine with visual aura.

Joshi et al. (2008) reported a 13-year-old boy with a history of ataxia
since early childhood who was diagnosed with GLUT1 deficiency syndrome
after onset of epilepsy at age 11 years. He had delayed psychomotor
development, early-onset ataxia, and hyperreflexia. He first developed a
seizure disorder at age 11 years, with staring spells, head jerking, eye
rolling, and loss of tone, which progressed to absence, myoclonic, and
atonic seizures. His cognitive and motor skills deteriorated during this
period. EEG showed moderate background slowing. Laboratory studies
showed decreased CSF glucose and lactate, consistent with GLUT1
deficiency syndrome. Genetic analysis identified a heterozygous mutation
in the SLC2A1 gene (R93W; 138140.0013). A ketogenic diet resulted in
complete seizure control with motor and cognitive improvement.

Zorzi et al. (2008) reported 3 unrelated Italian females with GLUT1
deficiency associated with paroxysmal movement disorders diagnosed in
early adulthood. None had a positive family history. All had global
developmental delay noted in infancy, and 2 had seizures beginning in
the first 6 months of life (myoclonic absence and complex partial
seizures, respectively). All had microcephaly, dysarthria, spasticity,
and moderate mental retardation. Paroxysmal movements included myoclonic
jerks, stiffening, and dystonic posturing. Two had exercise-induced
dystonia, 1 with choreoathetosis. Zorzi et al. (2008) noted that the
abnormal movements were consistent with paroxysmal dyskinesia, thus
expanding the phenotype associated with GLUT1 deficiency.

Suls et al. (2008) reported a 5-generation Belgian family segregating
paroxysmal exercise-induced dyskinesia and epilepsy. Three additional
smaller unrelated families with a similar phenotype were also observed.
Of the 22 affected individuals from all families, 19 (76%) had a history
of PED and 14 (56%) had a history of epilepsy; 11 (44%) had a history of
both. Three SLC2A1 mutation carriers were asymptomatic, indicating
reduced penetrance. The median age at onset of PED was 8 years (range,
3-30), and all patients had involvement of the legs. Precipitating
factors included exertion (89%), particularly prolonged brisk walking,
stress (39%), starvation (28%) and sleep deprivation (6%). All patients
had involvement of the legs: 9 (50%) reported involuntary movements
suggestive of choreoathetosis alone, 3 (17%) of dystonia, and 6 (33%) of
both. Choreoathetosis was described as uncontrollable rapid movements,
and dystonia as stiffening and cramps. PED made walking impossible and
caused falls in some individuals. The 14 mutation carriers with epilepsy
had a median age at onset of 2 years (range, 0-19). The seizure types
could be classified as absence (64%), generalized tonic-clonic seizures
without focal onset (50%), and complex and simple partial seizures
(14%). Most patients had seizure remission with antiepileptic drug
treatment. Most mutation carriers were of average intelligence or had
mild mental retardation. Four patients underwent formal neuropsychologic
testing and had a median IQ of 65 (45-79). EEG studies were often normal
(43%), but some showed interictal generalized epileptic discharges (29%)
and/or background slowing (5-10%). The mean CSF glucose level was 44
mg/dl (range, 34-64) and the mean CSF:plasma glucose was 0.52 (range,
0.47-0.60), indicating a mild decrease compared to controls. PET studies
suggested that disordered glucose metabolism in the corticostriate
pathways plays a role in PED, and that disordered glucose metabolism in
the frontal lobes plays a role in epilepsy. Three patients were
successfully treated with a ketogenic diet. Most patients reported that
PED and epilepsy became less severe when they grew older. The findings
indicated that both PED without epilepsy and PED with epilepsy can be
caused by mutations in the SLC2A1 gene. Suls et al. (2008) suggested
that attacks of PED may be caused by reduced glucose transport across
the blood-brain barrier, possibly when the energy demand of the brain
overcomes its supply after prolonged periods of exercise.

Rotstein et al. (2009) reported a 10-year-old boy with GLUT1 deficiency
syndrome who presented at age 2 years with onset of episodic ataxia and
slurred speech associated with unilateral muscle weakness. Laboratory
studies showed significantly decreased CSF glucose levels. He showed
gradual cognitive decline, progressive microcephaly, and ataxia during
childhood. Studies in patient erythrocytes showed about a 50% decrease
in glucose uptake compared to controls. Genetic analysis identified a de
novo heterozygous R93W mutation in the SLC2A1 gene (138140.0013).
Rotstein et al. (2009) noted that the phenotype in this patient was
reminiscent of alternating hemiplegia of childhood (104290).

Perez-Duenas et al. (2009) reported a 7-year-old girl with GLUT1
deficiency syndrome-2. She had delayed psychomotor development from
infancy, and presented at age 5 years with episodic flaccidity and loss
of ambulation. The episodes continued and were accompanied by gait
ataxia, dysarthria, dyskinesias, and choreic movements. Milder features
included action tremor, upper limb dysmetria, and ataxia. Brain MRI
showed moderately severe supratentorial cortico-subcortical atrophy, and
EEG showed mild diffuse slowing. CSF glucose was decreased. Institution
of a ketogenic diet resulted in clinical improvement of the movement
disorder and increased brain growth, although cognitive skills did not
improve. Genetic analysis identified a heterozygous de novo mutation in
the SLC2A1 gene (138140.0017).

Roubergue et al. (2011) reported a 20-year-old girl with GLUT1
deficiency syndrome-2, confirmed by genetic analysis, who presented at
age 11 years with action tremor and a 'jerky' voice. She had learning
disabilities, history of a single seizure at age 10.5, hyperreflexia,
unstable tandem walk, and foot PED. By age 20, the tremor had improved
and PED was stable. The patient's mother, who also carried the mutation,
had a similar phenotype, with tremor, PED, 'jerky' voice, unstable
tandem gait, and hyperreflexia. EMG in both patients showed an irregular
6- to 8.5-Hz postural hand tremor without myoclonus; CSF analysis in the
daughter showed mild glycorrhachia. Family history revealed that the
maternal grandmother and great-grandmother of the proband had hand
tremor, foot PED, and 'jerky' speech. Both patients refused treatment
with medication or a ketogenic diet. In a literature review, Roubergue
et al. (2011) found that about 6% of patients with GLUT1 mutations,
including their patients, had action tremor. Most patients with tremor
had additional mild neurologic disorders, such as learning disabilities,
seizures, cerebellar symptoms, and paroxysmal dystonia. The report
indicated that dystonic tremor can be a presenting symptom of mild GLUT1
deficiency.

- Clinical Variability

Weber et al. (2008) reported a 3-generation family in which 4 members
had childhood onset of episodic involuntary exertion-induced dystonic,
choreoathetotic, and ballistic movements associated with macrocytic
hemolytic anemia with reticulocytosis. One woman reported less frequent
symptoms since the age of 35, which disappeared completely after the age
of 45. Neuropsychologic evaluation revealed slight deficits in attention
concerning complex tasks and verbal memory in the 2 adults, mild
developmental delay in 1 child, and decreased cognitive function with an
IQ of 77 in the second child. The 2 younger patients developed seizures
in infancy and childhood, respectively, that were more frequent in the
morning before breakfast and improved after carbohydrate intake.
Ketogenic diets were beneficial in the younger patients. Electron
microscopy of the patients' red cells showed echinocytes, and
erythrocytes of all affected individuals had increased sodium and
decreased potassium. CSF revealed glucose levels at or below the lower
limit of normal.

Mullen et al. (2010) reported significant intrafamilial clinical
variability of GLUT1 deficiency syndrome in 2 unrelated families, one
with 9 mutation carriers spanning 2 generations and the other with 6
mutation carriers spanning 2 generations. Of 15 patients with SLC2A1
mutations, 12 had epilepsy, most commonly absence epilepsy, with onset
between ages 3 and 34 years. Eight patients had idiopathic generalized
epilepsies with absence seizures, 2 had myoclonic-astatic epilepsy, and
2 had focal epilepsy. Seven patients had subtle paroxysmal exertional
dyskinesia as the only manifestation, and 2 mutation carriers were
unaffected. Only 3 of 15 patients had mild intellectual disabilities.
Mullen et al. (2010) emphasized the phenotypic overlap with common forms
of idiopathic generalized epilepsy (see EIG12, 614847).

INHERITANCE

The transmission pattern in the family with PED reported by Munchau et
al. (2000) was consistent with autosomal dominant inheritance with
reduced penetrance.

MOLECULAR GENETICS

In affected members of the families reported by Margari et al. (2000)
and Munchau et al. (2000), Weber et al. (2008) identified 2 different
heterozygous mutations in the SLC2A1 gene (138140.0009 and 138140.0010,
respectively). Two additional families with PED did not have SLC2A1
mutations, suggesting genetic heterogeneity.

In affected members of a large Belgian family segregating PED and
epilepsy, Suls et al. (2008) identified a heterozygous missense mutation
in the GLUT1 gene (S95I; 138140.0012).

In affected members of a family with PED and hemolytic anemia, Weber et
al. (2008) identified a deletion in the SLC2A1 gene (138140.0008). Weber
et al. (2008) concluded that the dyskinesias resulted from an
exertion-induced energy deficit causing episodic dysfunction in the
basal ganglia. The hemolysis was demonstrated in vitro to result from
alterations in intracellular electrolytes caused by a cation leak
through mutant SLC2A1.

Schneider et al. (2009) identified 2 different de novo heterozygous
mutations in the GLUT1 gene (see, e.g., 138140.0015) in 2 of 10
unrelated Caucasian patients with paroxysmal exercise-induced
dyskinesias. One of the patients had childhood onset of absence
epilepsy.

*FIELD* RF
1. Brockmann, K.: The expanding phenotype of GLUT1-deficiency syndrome. Brain
Dev. 31: 545-552, 2009.

2. Joshi, C.; Greenberg, C. R.; De Vivo, D.; Wang, D.; Chan-Lui, W.;
Booth, F. A.: GLUT1 deficiency without epilepsy: yet another case. J.
Child Neurol. 23: 832-834, 2008.

3. Kamm, C.; Mayer, P.; Sharma, M.; Niemann, G.; Gasser, T.: New
family with paroxysmal exercise-induced dystonia and epilepsy. Mov.
Disord. 22: 873-877, 2007.

4. Margari, L.; Perniola, T.; Illiceto, G.; Ferrannini, E.; De Iaco,
M. G.; Presicci, A.; Santostasi, R.; Ventura, P.: Familial paroxysmal
exercise-induced dyskinesia and benign epilepsy: a clinical and neurophysiological
study of an uncommon disorder. Neurol. Sci. 21: 165-172, 2000.

5. Mullen, S. A.; Suls, A.; De Jonghe, P.; Berkovic, S. F.; Scheffer,
I. E.: Absence epilepsies with widely variable onset are a key feature
of familial GLUT1 deficiency. Neurology 75: 432-440, 2010.

6. Munchau, A.; Valente, E. M.; Shahidi, G. A.; Eunson, L. H.; Hanna,
M. G.; Quinn, N. P.; Schapira, A. H. V.; Wood, N. W.; Bhatia, K. P.
: A new family with paroxysmal exercise induced dystonia and migraine:
a clinical and genetic study. J. Neurol. Neurosurg. Psychiat. 68:
609-614, 2000.

7. Overweg-Plandsoen, W. C. G.; Groener, J. E. M.; Wang, D.; Onkenhout,
W.; Brouwer, O. F.; Bakker, H. D.; De Vivo, D. C.: GLUT-1 deficiency
without epilepsy--an exceptional case. J. Inherit. Metab. Dis. 26:
559-563, 2003.

8. Pascual, J. M.; Wang, D.; Lecumberri, B.; Yang, H.; Mao, X.; Yang,
R.; De Vivo, D. C.: GLUT1 deficiency and other glucose transporter
diseases. Europ. J. Endocrinol. 150: 627-633, 2004.

9. Perez-Duenas, B.; Prior, C.; Ma, Q.; Fernandez-Alvarez, E.; Setoain,
X.; Artuch, R.; Pascual, J. M.: Childhood chorea with cerebral hypotrophy:
a treatable GLUT1 energy failure syndrome. Arch. Neurol. 66: 1410-1414,
2009.

10. Plant, G. T.; Williams, A. C.; Earl, C. J.; Marsden, C. D.: Familial
paroxysmal dystonia induced by exercise. J. Neurol. Neurosurg. Psychiat. 47:
275-279, 1984.

11. Rotstein, M.; Doran, J.; Yang, H.; Ullner, P. M.; Engelstad, K.;
De Vivo, D. C.: GLUT1 deficiency and alternating hemiplegia of childhood. Neurology 73:
2042-2044, 2009.

12. Roubergue, A.; Apartis, E.; Mesnage, V.; Doummar, D.; Trocello,
J.-M.; Roze, E.; Taieb, G.; De Villemeur, T. B.; Vuillaumier-Barrot,
S.; Vidailhet, M.; Levy, R.: Dystonic tremor caused by mutation of
the glucose transporter gene GLUT1. J. Inherit. Metab. Dis. 34:
483-488, 2011.

13. Schneider, S. A.; Paisan-Ruiz, C.; Garcia-Gorostiaga, I.; Quinn,
N. P.; Weber, Y. G.; Lerche, H.; Hardy, J.; Bhatia, K. P.: GLUT1
gene mutations cause sporadic paroxysmal exercise-induced dyskinesias. Mov.
Disord. 24: 1684-1696, 2009.

14. Suls, A.; Dedeken, P.; Goffin, K.; Van Esch, H.; Dupont, P.; Cassiman,
D.; Kempfle, J.; Wuttke, T. V.; Weber, Y.; Lerche, H.; Afawi, Z.;
Vandenberghe, W.; and 15 others: Paroxysmal exercise-induced dyskinesia
and epilepsy is due to mutations in SLC2A1, encoding the glucose transporter
GLUT1. Brain 131: 1831-1844, 2008.

15. Wang, D.; Pascual, J. M.; Yang, H.; Engelstad, K.; Jhung, S.;
Sun, R. P.; De Vivo, D. C.: Glut-1 deficiency syndrome: clinical,
genetic, and therapeutic aspects. Ann. Neurol. 57: 111-118, 2005.

16. Weber, Y. G.; Storch, A.; Wuttke, T. V.; Brockmann, K.; Kempfle,
J.; Maljevic, S.; Margari, L.; Kamm, C.; Schneider, S. A.; Huber,
S. M.; Pekrun, A.; Roebling, R.; and 17 others: GLUT1 mutations
are a cause of paroxysmal exertion-induced dyskinesias and induce
hemolytic anemia by a cation leak. J. Clin. Invest. 118: 2157-2168,
2008.

17. Zorzi, G.; Castellotti, B.; Zibordi, F.; Gellera, C.; Nardocci,
N.: Paroxysmal movement disorders in GLUT1 deficiency syndrome. Neurology 71:
146-148, 2008.

*FIELD* CS
INHERITANCE:
Autosomal dominant

NEUROLOGIC:
[Central nervous system];
Dyskinesia, limb, exertion-induced;
Dystonia, limb, exercise-induced;
Flaccidity, episodic;
Choreoathetosis;
Ataxia, mild;
Seizures, particularly absence (in some patients);
EEG abnormalities;
Generalized spike wave discharges;
Generalized slowing;
Delayed psychomotor development;
Cognitive impairment;
Decreased CSF glucose;
Migraine headache (less common);
Cerebral atrophy;
[Behavioral/psychiatric manifestations];
Irritability (in 1 family)

HEMATOLOGY:
Macrocytic hemolytic anemia, appears in infancy (in 1 family);
Echinocytes;
Reticulocytosis;
Erythrocytes have defects in cation permeability

LABORATORY ABNORMALITIES:
Hypoglycorrhachia (low glucose in CSF);
Low-to-normal CSF lactate;
Increased serum bilirubin due to hemolysis

MISCELLANEOUS:
Onset in childhood;
Highly variable phenotype;
Favorable response to a ketogenic diet;
Incomplete penetrance;
Allelic disorder to GLUT1 deficiency syndrome 1 (606777)

MOLECULAR BASIS:
Caused by mutation in the solute carrier family 2 (facilitated glucose
transporter), member 1 gene (SLC2A1, 138140.0008)

*FIELD* CN
Cassandra L. Kniffin - updated: 6/30/2010

*FIELD* CD
Cassandra L. Kniffin: 6/24/2008

*FIELD* ED
joanna: 10/21/2011
ckniffin: 2/10/2011
ckniffin: 6/30/2010
joanna: 6/28/2010
ckniffin: 6/25/2008

*FIELD* CN
Cassandra L. Kniffin - updated: 1/8/2014
Cassandra L. Kniffin - updated: 10/4/2012
Cassandra L. Kniffin - updated: 8/2/2011
Cassandra L. Kniffin - updated: 2/23/2011
Cassandra L. Kniffin - updated: 6/30/2010
Cassandra L. Kniffin - updated: 6/25/2008

*FIELD* CD
Cassandra L. Kniffin: 6/24/2008

*FIELD* ED
carol: 01/17/2014
ckniffin: 1/8/2014
alopez: 6/10/2013
carol: 10/22/2012
ckniffin: 10/22/2012
carol: 10/22/2012
ckniffin: 10/4/2012
wwang: 8/9/2011
ckniffin: 8/2/2011
terry: 3/10/2011
wwang: 3/8/2011
ckniffin: 2/23/2011
carol: 7/7/2010
carol: 7/1/2010
ckniffin: 6/30/2010
wwang: 11/25/2008
ckniffin: 11/17/2008
carol: 8/22/2008
ckniffin: 6/25/2008

MIM 614847
*RECORD*
*FIELD* NO
614847
*FIELD* TI
#614847 EPILEPSY, IDIOPATHIC GENERALIZED, SUSCEPTIBILITY TO, 12; EIG12
*FIELD* TX
A number sign (#) is used with this entry because susceptibility to
read moreidiopathic generalized epilepsy-12 (EIG12) is conferred by heterozygous
mutation in the SLC2A1 gene (138140) on chromosome 1p34.

Allelic disorders with overlapping features include GLUT1 deficiency
syndrome-1 (GLUT1DS1; 606777), GLUT1 deficiency syndrome-2 (GLUT1DS2;
612126), and dystonia-9 (DYT9; 601042).

For a general phenotypic description and a discussion of genetic
heterogeneity of idiopathic generalized epilepsy, see EIG1 (600669).

CLINICAL FEATURES

Suls et al. (2009) identified heterozygous mutations in the SLC2A1 gene
in 4 (12%) of 34 patients with early-onset absence epilepsy before age 4
years. CSF glucose levels were not available from any of the patients.
One of the patients had no additional abnormalities and normal
development. However, clinical review of these patients after diagnosis
showed that 3 had mild to moderate mental retardation, 2 had mild
ataxia, and 1 had myoclonus and exercise-induced paroxysmal dyskinesia.
None had microcephaly. Two patients inherited missense mutations from
parents with later-onset absence epilepsy.

Mullen et al. (2010) reported significant intrafamilial clinical
variability in 2 unrelated families with SLC2A1 mutations: 1 with 9
mutation carriers spanning 2 generations and the other with 6 mutation
carriers spanning 2 generations. Of 15 patients with SLC2A1 mutations,
12 had epilepsy, most commonly absence epilepsy, with onset between ages
3 and 34 years. Eight patients had idiopathic generalized epilepsies
with absence seizures, 2 had myoclonic-astatic epilepsy, and 2 had focal
epilepsy. Seven patients had subtle paroxysmal exertional dyskinesia as
the only manifestation, and 2 mutation carriers were unaffected. Only 3
of 15 patients had mild intellectual disabilities. Mullen et al. (2010)
emphasized the phenotypic overlap with common forms of idiopathic
generalized epilepsy.

Striano et al. (2012) reported a large Italian family in which 9
individuals spanning 3 generations had various forms of epilepsy. The
age at seizure onset ranged from early childhood to 23 years. All had
generalized seizures, mainly typical absence seizures, and EEG showed
regular, symmetric discharges of 3 to 3.5 Hz spike wave complexes.
Seizures typically remitted 2 to 5 years after onset, although 1 patient
later developed juvenile myoclonic epilepsy. Most showed a favorable
response to pharmacologic treatment. None of the patients had other
neurologic manifestations, including movement disorders.

INHERITANCE

The transmission pattern in the family with idiopathic generalized
epilepsy reported by Striano et al. (2012) was consistent with autosomal
dominant inheritance and incomplete penetrance (67%).

MOLECULAR GENETICS

Suls et al. (2009) reported a 28-year-old woman with early-onset absence
epilepsy at age 3 years and generalized tonic-clonic seizures at age 7.
She had normal intelligence and remission of seizures with medication at
age 7. CSF glucose levels were not available. Genetic analysis
identified a heterozygous mutation in the SLC2A1 gene (138140.0020). The
findings indicated that SLC2A1 mutations may contribute to relatively
mild forms of epilepsy.

In 1 of 95 families with EIG, Striano et al. (2012) identified a
heterozygous missense mutation in the SLC2A1 gene (R232C; 138140.0019).
All 8 living patients with seizures in this family carried the mutation,
which was also found in 4 healthy adult family members, yielding a
penetrance of 67%. In vitro functional studies showed that the mutant
protein was expressed at the cell surface but had mildly decreased
glucose uptake (70%) compared to wildtype. The findings suggested that
GLUT1 deficiency is a rare cause of typical EIG, and also expanded the
phenotypic spectrum associated with mutations in the SLC2A1 gene.

By direct sequencing of the SLC2A1 gene, Arsov et al. (2012) identified
variants not previously reported in databases of normal human genetic
variation in 9 of 504 probands from Israel and Australia with idiopathic
generalized epilepsy and in 1 of 470 controls (p = 0.02). All variants
occurred at highly conserved residues, but in vitro functional
expression studies in Xenopus oocytes indicated variable effects. Three
variants (see, e.g., R458W, 138140.0021 and N411S, 138140.0022) caused a
marked decrease in glucose transport, 4 variants caused a mild reduction
in glucose transport, and 2 variants, including the 1 identified in the
control individual, had no effect on glucose transport; the effect of
the remaining variant could not be determined. Segregation with
incomplete penetrance in families was observed for 2 of the variants
that had a marked effect on protein function; the third variant occurred
de novo. In contrast, segregation was not strong for variants with mild
functional effects: several carriers of the mild variants were
unaffected, 1 homozygous carrier was unaffected, and 1 affected
individual did not carry a variant. Arsov et al. (2012) concluded that
variants in the GLUT1 gene, particularly those with mild functional
effects, may act as susceptibility alleles that contribute to the
multifactorial etiology of EIG in about 1% of cases.

*FIELD* RF
1. Arsov, T.; Mullen, S. A.; Rogers, S.; Phillips, A. M.; Lawrence,
K. M.; Damiano, J. A.; Goldberg-Stern, H.; Afawi, Z.; Kivity, S.;
Trager, C.; Petrou, S.; Berkovic, S. F.; Scheffer, I. E.: Glucose
transporter 1 deficiency in the idiopathic generalized epilepsies. Ann.
Neurol. 72: 807-815, 2012.

2. Mullen, S. A.; Suls, A.; De Jonghe, P.; Berkovic, S. F.; Scheffer,
I. E.: Absence epilepsies with widely variable onset are a key feature
of familial GLUT1 deficiency. Neurology 75: 432-440, 2010.

3. Striano, P.; Weber, Y. G.; Toliat, M. R.; Schubert, J.; Leu, C.;
Chaimana, R.; Baulac, S.; Guerrero, R.; LeGuern, E.; Lehesjoki, A.-E.;
Polvi, A.; Robbiano, A.; Serratosa, J. M.; Guerrini, R.; Nurnberg,
P.; Sander, T.; Zara, F.; Lerche, H.; Marini, C. GLUT1 mutations
are a rare cause of familial idiopathic generalized epilepsy. Neurology 78:
557-562, 2012.

4. Suls, A.; Mullen, S. A.; Weber, Y. G.; Verhaert, K.; Ceulemans,
B.; Guerrini, R.; Wuttke, T. V.; Salvo-Vargas, A.; Deprez, L.; Claes,
L. R. F.; Jordanova, A.; Berkovic, S. F.; Lerche, H.; De Jonghe, P.;
Scheffer, I. E.: Early-onset absence epilepsy caused by mutations
in the glucose transporter GLUT1. Ann. Neurol. 66: 415-419, 2009.

*FIELD* CS
INHERITANCE:
Autosomal dominant

NEUROLOGIC:
[Central nervous system];
Seizures, absence;
Seizures, juvenile myoclonic;
Seizures, generalized tonic-clonic

MISCELLANEOUS:
Onset in first to second decade;
Seizures may remit with age (in some patients);
Incomplete penetrance

MOLECULAR BASIS:
Caused by mutation in the solute carrier family 2 (facilitated glucose
transporter), member 1 gene (SLC2A1, 138140.0019)

*FIELD* CD
Cassandra L. Kniffin: 10/4/2012

*FIELD* ED
joanna: 10/25/2012
ckniffin: 10/4/2012

*FIELD* CN
Cassandra L. Kniffin - updated: 1/8/2014
Cassandra L. Kniffin - updated: 10/18/2012

*FIELD* CD
Cassandra L. Kniffin: 10/4/2012

*FIELD* ED
carol: 01/17/2014
ckniffin: 1/8/2014
carol: 10/22/2012
ckniffin: 10/18/2012
carol: 10/9/2012
ckniffin: 10/4/2012

RBCC Red Blood Cell Collection

Full text data of SLC2A1