RBCC Red Blood Cell Collection

GBE1 [Confidence: low (only semi-automatic identification from reviews)]
1,4-alpha-glucan-branching enzyme; 2.4.1.18 (Brancher enzyme; Glycogen-branching enzyme)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt Q04446
ID GLGB_HUMAN Reviewed; 702 AA.
AC Q04446; B3KWV3; Q96EN0;
DT 01-JUN-1994, integrated into UniProtKB/Swiss-Prot.
read moreDT 16-NOV-2011, sequence version 3.
DT 22-JAN-2014, entry version 139.
DE RecName: Full=1,4-alpha-glucan-branching enzyme;
DE EC=2.4.1.18;
DE AltName: Full=Brancher enzyme;
DE AltName: Full=Glycogen-branching enzyme;
GN Name=GBE1;
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], AND VARIANT VAL-334.
RC TISSUE=Liver;
RX PubMed=8463281;
RA Thon V.J., Khalil M., Cannon J.F.;
RT "Isolation of human glycogen branching enzyme cDNAs by screening
RT complementation in yeast.";
RL J. Biol. Chem. 268:7509-7513(1993).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Testis;
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].
RX PubMed=16641997; DOI=10.1038/nature04728;
RA Muzny D.M., Scherer S.E., Kaul R., Wang J., Yu J., Sudbrak R.,
RA Buhay C.J., Chen R., Cree A., Ding Y., Dugan-Rocha S., Gill R.,
RA Gunaratne P., Harris R.A., Hawes A.C., Hernandez J., Hodgson A.V.,
RA Hume J., Jackson A., Khan Z.M., Kovar-Smith C., Lewis L.R.,
RA Lozado R.J., Metzker M.L., Milosavljevic A., Miner G.R., Morgan M.B.,
RA Nazareth L.V., Scott G., Sodergren E., Song X.-Z., Steffen D., Wei S.,
RA Wheeler D.A., Wright M.W., Worley K.C., Yuan Y., Zhang Z., Adams C.Q.,
RA Ansari-Lari M.A., Ayele M., Brown M.J., Chen G., Chen Z.,
RA Clendenning J., Clerc-Blankenburg K.P., Chen R., Chen Z., Davis C.,
RA Delgado O., Dinh H.H., Dong W., Draper H., Ernst S., Fu G.,
RA Gonzalez-Garay M.L., Garcia D.K., Gillett W., Gu J., Hao B.,
RA Haugen E., Havlak P., He X., Hennig S., Hu S., Huang W., Jackson L.R.,
RA Jacob L.S., Kelly S.H., Kube M., Levy R., Li Z., Liu B., Liu J.,
RA Liu W., Lu J., Maheshwari M., Nguyen B.-V., Okwuonu G.O., Palmeiri A.,
RA Pasternak S., Perez L.M., Phelps K.A., Plopper F.J., Qiang B.,
RA Raymond C., Rodriguez R., Saenphimmachak C., Santibanez J., Shen H.,
RA Shen Y., Subramanian S., Tabor P.E., Verduzco D., Waldron L., Wang J.,
RA Wang J., Wang Q., Williams G.A., Wong G.K.-S., Yao Z., Zhang J.,
RA Zhang X., Zhao G., Zhou J., Zhou Y., Nelson D., Lehrach H.,
RA Reinhardt R., Naylor S.L., Yang H., Olson M., Weinstock G.,
RA Gibbs R.A.;
RT "The DNA sequence, annotation and analysis of human chromosome 3.";
RL Nature 440:1194-1198(2006).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANTS SER-265 AND
RP VAL-334.
RC TISSUE=B-cell;
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 PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-173, AND MASS
RP SPECTROMETRY.
RX PubMed=15592455; DOI=10.1038/nbt1046;
RA Rush J., Moritz A., Lee K.A., Guo A., Goss V.L., Spek E.J., Zhang H.,
RA Zha X.-M., Polakiewicz R.D., Comb M.J.;
RT "Immunoaffinity profiling of tyrosine phosphorylation in cancer
RT cells.";
RL Nat. Biotechnol. 23:94-101(2005).
RN [6]
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 [7]
RP VARIANTS GSD4 PRO-224; LEU-257; SER-329 AND CYS-515.
RX PubMed=8613547; DOI=10.1172/JCI118517;
RA Bao Y., Kishnani P., Wu J.Y., Chen Y.T.;
RT "Hepatic and neuromuscular forms of glycogen storage disease type IV
RT caused by mutations in the same glycogen-branching enzyme gene.";
RL J. Clin. Invest. 97:941-948(1996).
RN [8]
RP VARIANT GSD4 GLN-524.
RX PubMed=10545044; DOI=10.1016/S0960-8966(99)00040-1;
RA Bruno C., DiRocco M., Lamba L.D., Bado M., Marino C., Tsujino S.,
RA Shanske S., Stella G., Minetti C., van Diggelen O.P., DiMauro S.;
RT "A novel missense mutation in the glycogen branching enzyme gene in a
RT child with myopathy and hepatopathy.";
RL Neuromuscul. Disord. 9:403-407(1999).
RN [9]
RP VARIANTS APBD HIS-515 AND GLN-524.
RX PubMed=10762170;
RX DOI=10.1002/1531-8249(200004)47:4<536::AID-ANA22>3.3.CO;2-B;
RA Ziemssen F., Sindern E., Schroder J.M., Shin Y.S., Zange J.,
RA Kilimann M.W., Malin J.P., Vorgerd M.;
RT "Novel missense mutations in the glycogen-branching enzyme gene in
RT adult polyglucosan body disease.";
RL Ann. Neurol. 47:536-540(2000).
RN [10]
RP VARIANTS GSD4 GLN-524; ARG-545 AND ARG-628.
RX PubMed=15452297;
RA Bruno C., van Diggelen O.P., Cassandrini D., Gimpelev M., Giuffre B.,
RA Donati M.A., Introvini P., Alegria A., Assereto S., Morandi L.,
RA Mora M., Tonoli E., Mascelli S., Traverso M., Pasquini E., Bado M.,
RA Vilarinho L., van Noort G., Mosca F., DiMauro S., Zara F., Minetti C.;
RT "Clinical and genetic heterogeneity of branching enzyme deficiency
RT (glycogenosis type IV).";
RL Neurology 63:1053-1058(2004).
CC -!- FUNCTION: Required for sufficient glycogen accumulation. The alpha
CC 1-6 branches of glycogen play an important role in increasing the
CC solubility of the molecule and, consequently, in reducing the
CC osmotic pressure within cells.
CC -!- CATALYTIC ACTIVITY: Transfers a segment of a (1->4)-alpha-D-glucan
CC chain to a primary hydroxy group in a similar glucan chain.
CC -!- PATHWAY: Glycan biosynthesis; glycogen biosynthesis.
CC -!- SUBUNIT: Monomer.
CC -!- TISSUE SPECIFICITY: Highest levels found in liver and muscle.
CC -!- DISEASE: Glycogen storage disease 4 (GSD4) [MIM:232500]: A
CC metabolic disorder characterized by the accumulation of an
CC amylopectin-like polysaccharide. The typical clinical
CC manifestation is liver disease of childhood, progressing to lethal
CC hepatic cirrhosis. Most children with this condition die before
CC two years of age. However, the liver disease is not always
CC progressive. No treatment apart from liver transplantation has
CC been found to prevent progression of the disease. There is also a
CC neuromuscular form of glycogen storage disease type 4 that varies
CC in onset (perinatal, congenital, juvenile, or adult) and severity.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- DISEASE: Note=Neuromuscular perinatal glycogen storage disease
CC type 4 is associated with non-immune hydrops fetalis, a
CC generalized edema of the fetus with fluid accumulation in the body
CC cavities due to non-immune causes. Non-immune hydrops fetalis is
CC not a diagnosis in itself but a symptom, a feature of many genetic
CC disorders, and the end-stage of a wide variety of disorders.
CC -!- DISEASE: Adult polyglucosan body disease (APBD) [MIM:263570]: A
CC late-onset, slowly progressive disorder affecting the central and
CC peripheral nervous systems. Patients typically present after age
CC 40 years with a variable combination of cognitive impairment,
CC pyramidal tetraparesis, peripheral neuropathy, and neurogenic
CC bladder. Other manifestations include cerebellar dysfunction and
CC extrapyramidal signs. The pathologic hallmark of APBD is the
CC widespread accumulation of round, intracellular polyglucosan
CC bodies throughout the nervous system, which are confined to
CC neuronal and astrocytic processes. Note=The disease is caused by
CC mutations affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the glycosyl hydrolase 13 family. GlgB
CC subfamily.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/GBE1";
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DR EMBL; L07956; AAA58642.1; -; mRNA.
DR EMBL; AK125918; BAG54265.1; -; mRNA.
DR EMBL; AC017015; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC025029; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC099049; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC012098; AAH12098.1; -; mRNA.
DR PIR; A46075; A46075.
DR RefSeq; NP_000149.3; NM_000158.3.
DR UniGene; Hs.436062; -.
DR PDB; 4BZY; X-ray; 2.75 A; A/B/C=1-702.
DR PDBsum; 4BZY; -.
DR ProteinModelPortal; Q04446; -.
DR SMR; Q04446; 31-699.
DR IntAct; Q04446; 4.
DR MINT; MINT-1415803; -.
DR STRING; 9606.ENSP00000410833; -.
DR CAZy; CBM48; Carbohydrate-Binding Module Family 48.
DR CAZy; GH13; Glycoside Hydrolase Family 13.
DR PhosphoSite; Q04446; -.
DR DMDM; 67465046; -.
DR PaxDb; Q04446; -.
DR PRIDE; Q04446; -.
DR DNASU; 2632; -.
DR Ensembl; ENST00000429644; ENSP00000410833; ENSG00000114480.
DR GeneID; 2632; -.
DR KEGG; hsa:2632; -.
DR CTD; 2632; -.
DR GeneCards; GC03M081621; -.
DR HGNC; HGNC:4180; GBE1.
DR HPA; HPA038073; -.
DR HPA; HPA038074; -.
DR HPA; HPA038075; -.
DR MIM; 232500; phenotype.
DR MIM; 263570; phenotype.
DR MIM; 607839; gene.
DR neXtProt; NX_Q04446; -.
DR Orphanet; 206583; Adult polyglucosan body disease.
DR Orphanet; 308712; Glycogen storage disease due to glycogen branching enzyme deficiency, adult neuromuscular form.
DR Orphanet; 308684; Glycogen storage disease due to glycogen branching enzyme deficiency, childhood combined hepatic and myopathic form.
DR Orphanet; 308698; Glycogen storage disease due to glycogen branching enzyme deficiency, childhood neuromuscular form.
DR Orphanet; 308670; Glycogen storage disease due to glycogen branching enzyme deficiency, congenital neuromuscular form.
DR Orphanet; 308655; Glycogen storage disease due to glycogen branching enzyme deficiency, fatal perinatal neuromuscular form.
DR Orphanet; 308638; Glycogen storage disease due to glycogen branching enzyme deficiency, non progressive hepatic form.
DR Orphanet; 308621; Glycogen storage disease due to glycogen branching enzyme deficiency, progressive hepatic form.
DR PharmGKB; PA28594; -.
DR eggNOG; COG0296; -.
DR HOVERGEN; HBG051734; -.
DR InParanoid; Q04446; -.
DR KO; K00700; -.
DR OMA; EIDPYLK; -.
DR BioCyc; MetaCyc:HS03772-MONOMER; -.
DR Reactome; REACT_111217; Metabolism.
DR UniPathway; UPA00164; -.
DR ChiTaRS; GBE1; human.
DR GeneWiki; GBE1; -.
DR GenomeRNAi; 2632; -.
DR NextBio; 10376; -.
DR PRO; PR:Q04446; -.
DR ArrayExpress; Q04446; -.
DR Bgee; Q04446; -.
DR CleanEx; HS_GBE1; -.
DR Genevestigator; Q04446; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0003844; F:1,4-alpha-glucan branching enzyme activity; TAS:ProtInc.
DR GO; GO:0043169; F:cation binding; IEA:InterPro.
DR GO; GO:0004553; F:hydrolase activity, hydrolyzing O-glycosyl compounds; IEA:InterPro.
DR GO; GO:0006006; P:glucose metabolic process; TAS:Reactome.
DR GO; GO:0005978; P:glycogen biosynthetic process; TAS:Reactome.
DR GO; GO:0044281; P:small molecule metabolic process; TAS:Reactome.
DR Gene3D; 2.60.40.10; -; 1.
DR Gene3D; 2.60.40.1180; -; 1.
DR Gene3D; 3.20.20.80; -; 1.
DR InterPro; IPR006048; A-amylase_b_C.
DR InterPro; IPR006407; GlgB.
DR InterPro; IPR015902; Glyco_hydro_13.
DR InterPro; IPR013780; Glyco_hydro_13_b.
DR InterPro; IPR006047; Glyco_hydro_13_cat_dom.
DR InterPro; IPR004193; Glyco_hydro_13_N.
DR InterPro; IPR013781; Glyco_hydro_catalytic_dom.
DR InterPro; IPR017853; Glycoside_hydrolase_SF.
DR InterPro; IPR013783; Ig-like_fold.
DR InterPro; IPR014756; Ig_E-set.
DR PANTHER; PTHR10357; PTHR10357; 1.
DR Pfam; PF00128; Alpha-amylase; 1.
DR Pfam; PF02806; Alpha-amylase_C; 1.
DR Pfam; PF02922; CBM_48; 1.
DR PIRSF; PIRSF000463; GlgB; 1.
DR SUPFAM; SSF51445; SSF51445; 1.
DR SUPFAM; SSF81296; SSF81296; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Complete proteome; Disease mutation;
KW Glycogen biosynthesis; Glycogen storage disease; Glycosyltransferase;
KW Phosphoprotein; Polymorphism; Reference proteome; Transferase.
FT CHAIN 1 702 1,4-alpha-glucan-branching enzyme.
FT /FTId=PRO_0000188775.
FT ACT_SITE 357 357 Nucleophile (By similarity).
FT ACT_SITE 412 412 Proton donor (By similarity).
FT MOD_RES 173 173 Phosphotyrosine.
FT VARIANT 190 190 R -> G (in dbSNP:rs2229519).
FT /FTId=VAR_022109.
FT VARIANT 224 224 L -> P (in GSD4; loss of activity).
FT /FTId=VAR_022429.
FT VARIANT 257 257 F -> L (in GSD4; loss of activity).
FT /FTId=VAR_022430.
FT VARIANT 265 265 T -> S (in dbSNP:rs17856389).
FT /FTId=VAR_034747.
FT VARIANT 329 329 Y -> S (in GSD4; non-progressive form;
FT 50% residual activity).
FT /FTId=VAR_022431.
FT VARIANT 334 334 I -> V (in dbSNP:rs2172397).
FT /FTId=VAR_034748.
FT VARIANT 507 507 T -> A (in dbSNP:rs2228389).
FT /FTId=VAR_034749.
FT VARIANT 515 515 R -> C (in GSD4; loss of activity).
FT /FTId=VAR_022432.
FT VARIANT 515 515 R -> H (in APBD).
FT /FTId=VAR_022433.
FT VARIANT 524 524 R -> Q (in GSD4 and APBD).
FT /FTId=VAR_022434.
FT VARIANT 545 545 H -> R (in GSD4).
FT /FTId=VAR_022435.
FT VARIANT 628 628 H -> R (in GSD4; childhood neuromuscular
FT form; 15 to 25% residual activity).
FT /FTId=VAR_022436.
FT CONFLICT 88 88 C -> S (in Ref. 1; AAA58642).
FT HELIX 45 62
FT HELIX 66 69
FT HELIX 70 74
FT STRAND 76 80
FT STRAND 86 91
FT STRAND 96 102
FT HELIX 103 105
FT STRAND 109 113
FT STRAND 121 126
FT STRAND 141 147
FT STRAND 153 156
FT STRAND 174 176
FT STRAND 195 204
FT STRAND 207 212
FT HELIX 216 222
FT HELIX 224 230
FT STRAND 234 239
FT HELIX 246 248
FT STRAND 254 259
FT HELIX 261 263
FT HELIX 266 278
FT STRAND 282 288
FT STRAND 296 300
FT TURN 301 304
FT STRAND 305 307
FT STRAND 309 311
FT HELIX 315 317
FT TURN 320 323
FT HELIX 332 347
FT STRAND 353 357
FT HELIX 359 363
FT HELIX 387 403
FT STRAND 408 411
FT TURN 418 421
FT HELIX 424 426
FT STRAND 432 435
FT HELIX 438 449
FT HELIX 452 454
FT HELIX 457 465
FT STRAND 473 475
FT HELIX 481 483
FT HELIX 490 495
FT HELIX 496 500
FT HELIX 511 530
FT STRAND 533 538
FT HELIX 541 543
FT HELIX 554 556
FT HELIX 567 570
FT HELIX 577 594
FT STRAND 597 599
FT STRAND 603 608
FT TURN 609 612
FT STRAND 613 618
FT STRAND 621 626
FT STRAND 633 642
FT STRAND 644 651
FT HELIX 655 657
FT STRAND 669 673
FT STRAND 679 687
FT STRAND 691 698
SQ SEQUENCE 702 AA; 80474 MW; DEF534C821A72323 CRC64;
MAAPMTPAAR PEDYEAALNA ALADVPELAR LLEIDPYLKP YAVDFQRRYK QFSQILKNIG
ENEGGIDKFS RGYESFGVHR CADGGLYCKE WAPGAEGVFL TGDFNGWNPF SYPYKKLDYG
KWELYIPPKQ NKSVLVPHGS KLKVVITSKS GEILYRISPW AKYVVREGDN VNYDWIHWDP
EHSYEFKHSR PKKPRSLRIY ESHVGISSHE GKVASYKHFT CNVLPRIKGL GYNCIQLMAI
MEHAYYASFG YQITSFFAAS SRYGTPEELQ ELVDTAHSMG IIVLLDVVHS HASKNSADGL
NMFDGTDSCY FHSGPRGTHD LWDSRLFAYS SWEILRFLLS NIRWWLEEYR FDGFRFDGVT
SMLYHHHGVG QGFSGDYSEY FGLQVDEDAL TYLMLANHLV HTLCPDSITI AEDVSGMPAL
CSPISQGGGG FDYRLAMAIP DKWIQLLKEF KDEDWNMGDI VYTLTNRRYL EKCIAYAESH
DQALVGDKSL AFWLMDAEMY TNMSVLTPFT PVIDRGIQLH KMIRLITHGL GGEGYLNFMG
NEFGHPEWLD FPRKGNNESY HYARRQFHLT DDDLLRYKFL NNFDRDMNRL EERYGWLAAP
QAYVSEKHEG NKIIAFERAG LLFIFNFHPS KSYTDYRVGT ALPGKFKIVL DSDAAEYGGH
QRLDHSTDFF SEAFEHNGRP YSLLVYIPSR VALILQNVDL PN
//

MIM 232500
*RECORD*
*FIELD* NO
232500
*FIELD* TI
#232500 GLYCOGEN STORAGE DISEASE IV
;;GSD IV; GSD4;;
GLYCOGEN BRANCHING ENZYME DEFICIENCY;;
read moreGBE1 DEFICIENCY;;
ANDERSEN DISEASE;;
BRANCHER DEFICIENCY;;
GLYCOGENOSIS IV;;
AMYLOPECTINOSIS;;
CIRRHOSIS, FAMILIAL, WITH DEPOSITION OF ABNORMAL GLYCOGEN
GSD IV, CLASSIC HEPATIC, INCLUDED;;
GSD IV, NONPROGRESSIVE HEPATIC, INCLUDED;;
GSD IV, NEUROMUSCULAR FORM, FATAL PERINATAL, INCLUDED;;
GSD IV, NEUROMUSCULAR FORM, CONGENITAL, INCLUDED;;
GSD IV, NEUROMUSCULAR FORM, CHILDHOOD, INCLUDED;;
GSD IV, NEUROMUSCULAR FORM, ADULT, WITH ISOLATED MYOPATHY, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because glycogen storage
disease type IV (GSD IV) is caused by mutation in the gene encoding the
glycogen branching enzyme (GBE1; 607839).

Mutation in the same gene causes an allelic disorder, adult polyglucosan
body disease (APED; 263570).

CLINICAL FEATURES

Glycogen storage disease type IV is a clinically heterogeneous disorder.
The typical 'classic' hepatic presentation is liver disease of
childhood, progressing to lethal cirrhosis. The neuromuscular
presentation of GSD IV is distinguished by age at onset into 4 groups:
perinatal, presenting as fetal akinesia deformation sequence (FADS) and
perinatal death; congenital, with hypotonia, neuronal involvement, and
death in early infancy; childhood, with myopathy or cardiomyopathy; and
adult, with isolated myopathy or adult polyglucosan body disease (Bruno
et al., 2004). The enzyme deficiency results in tissue accumulation of
abnormal glycogen with fewer branching points and longer outer branches,
resembling an amylopectin-like structure, also known as polyglucosan
(Tay et al., 2004).

Bruno et al. (2007) provided a review of the neuromuscular forms of
glycogen branching enzyme deficiency.

- Classic Hepatic Form

Andersen (1956) originally reported GSD IV as 'familial cirrhosis of the
liver with storage of abnormal glycogen.' Brown and Brown (1966)
determined that the defect in GSD IV was a deficiency of the
alpha-1,4-glucan branching enzyme.

Bao et al. (1996) noted that the most common form of GSD IV presents in
the first 18 months of life with failure to thrive, hepatosplenomegaly,
and liver cirrhosis. There is progression to portal hypertension,
ascites, and liver failure, leading to death by age 5 years. A simple
iodine test shows formation of a blue colored complex of glycogen and
iodine. The liver shows the main involvement, resulting from a defect of
amylo(1,4 to 1,6) transglucosidase (brancher enzyme).

- Nonprogressive Hepatic Form

Less frequently, patients may have liver dysfunction without liver
failure, referred to as 'nonprogressive hepatic GSD IV.' Greene et al.
(1988) reported a 5-year-old boy who was first noted to have elevated
serum transaminase levels and hepatomegaly at age 2 years following an
acute febrile illness. Successive liver biopsies showed hepatocellular
periodic-acid Schiff-positive diastase-resistant inclusions and hepatic
fibrosis that was nonprogressive over 3 years. Enzymatic assays showed
deficient branching enzyme in liver, skeletal muscle, and skin
fibroblasts. The child showed normal growth and development.

McConkie-Rosell et al. (1996) found that 6 patients with nonprogressive
hepatic GSD IV did not develop progressive liver cirrhosis, cardiac, or
neurologic involvement, despite residual branching enzyme activity in
skin fibroblasts that was indistinguishable from patients with more
severe forms of GSD IV. The authors concluded that residual enzyme
activity could not be used to predict the clinical course in GSD IV,
that not all patients require liver transplant, and that caution should
be used in genetic counseling.

- Fatal Perinatal Neuromuscular Form

Alegria et al. (1999) reported hydrops fetalis as a presenting
manifestation of glycogen storage disease type IV. The infant, delivered
by cesarean section at 34 weeks, had generalized edema, severe
hypotonia, and arthrogryposis of the lower limbs at birth. There were no
signs of cirrhosis or liver failure. She died on the fourth day of life.

Cox et al. (1999) reported 3 sib fetuses who were shown to have type IV
glycogen storage disease by pathologic and biochemical studies, with
onset of hydrops, limb contractures, and akinesia in the early second
trimester.

- Congenital Neuromuscular Form

Zellweger et al. (1972) reported infantile onset of GSD IV with
hypotonia.

McMaster et al. (1979) reported a 30-month old girl with GSD IV in whom
extensive involvement of the nervous system was found at autopsy. In a
review of the literature, the authors noted that approximately 50% of
GSD IV patients have neuromuscular signs and symptoms.

Tang et al. (1994) reported a neonate with GSD IV who presented with
severe hypotonia and dilated cardiomyopathy. The classic clinical
manifestation of liver cirrhosis was not present, although
amylopectin-like inclusions were found in hepatocytes. He died of
cardiorespiratory failure at 4 weeks of age. In the child reported by
Tang et al. (1994), Bao et al. (1996) identified a mutation in the GBE1
gene (607839.0001).

Tay et al. (2004) reported 2 unrelated patients with the congenital
variant of GSD IV confirmed by mutation in the GBE1 gene (607839.0008).
Both pregnancies were complicated by polyhydramnios, and both neonates
showed hypotonia and poor respiratory effort at birth. Only 1 had
contractures. Both died within the first weeks of life. Branching enzyme
activities were 0.9% and 0.8% of normal controls. Postmortem examination
of 1 infant showed pale, atrophic skeletal muscles, and PAS-positive,
diastase-resistant globules in liver, heart, skeletal muscle, and
neurons of the brain and spinal cord.

Bruno et al. (2004) reported 2 sibs with congenital GSD IV confirmed by
mutation in the GBE1 gene (607839.0011; 607839.0012). In both cases,
pregnancy was complicated by polyhydramnios, reduced fetal movements,
and fetal hydrops. At birth, both infants had severe hypotonia,
hyporeflexia, and no spontaneous respiration. Death occurred at ages 4
months and 4 weeks, respectively, due to cardiorespiratory failure.
Autopsy showed hypertrophy of the left cardiac ventricle. Residual GBE1
activity in fibroblasts was less than 5%.

Assereto et al. (2007) reported 2 unrelated newborns who showed severe
hypotonia at birth and died of cardiorespiratory failure at ages 4 and
12 weeks, respectively. Both pregnancies were complicated by
polyhydramnios and reduced fetal movements. One infant had equinovarus
feet with flexion contractures. GBE1 activity in cultured fibroblasts
was less than 5% in both cases. Molecular analysis identified a
homozygous null mutation in the GBE1 gene in each patient (607839.0017
and 607839.0018, respectively).

- Childhood Neuromuscular Form

Guerra et al. (1986) reported an 8-year-old child with Andersen
syndrome. Servidei et al. (1987) reported a 7.5-year-old girl with
exercise intolerance and exertional dyspnea. She developed congestive
heart failure and died 1 year later. Endomyocardial biopsy showed
abundant PAS-positive, diastase-resistant cytoplasmic deposits that were
also seen in muscle, skin, and liver specimens. Glycogen branching
enzyme was absent in all postmortem tissues.

In 3 Turkish male sibs suffering from chronic progressive myopathy,
Reusche et al. (1992) identified a mild juvenile form of type IV
glycogenosis which was confirmed by the finding of profound deficiency
of the brancher enzyme. They pointed out that when polyglucosan
inclusions are observed in myofibers, it is mandatory to examine muscle
tissue for brancher enzyme activity since this enzyme activity was
normal in circulating erythrocytes and leukocytes in all 3 affected sibs
and their parents; the disorder in this family was limited to muscle
tissues.

Schroder et al. (1993) reported a case of juvenile type IV glycogenosis
with total branching enzyme deficiency in skeletal muscle and liver
tissue in a male who presented with severe myopathy, dilated
cardiomyopathy, heart failure, dysmorphic features, and subclinical
neuropathy. He died from sudden cardiac death at age 19. His 15-year-old
brother had similar clinical and histologic findings.

Bruno et al. (2004) reported a 4-year-old boy with childhood
neuromuscular GSD IV confirmed by mutation in the GBE1 gene
(607839.0006; 607839.0013). He developed generalized hypotonia at age 11
months; at age 3 years, he had myopathic face, muscular hypotrophy and
hypotonia, and waddling gait with hyperlordosis. Serum creatine kinase
was normal, and there were no signs of liver involvement. Residual GBE1
activity in fibroblasts was 15 to 25%.

- Adult Neuromuscular Form with Isolated Myopathy

Ferguson et al. (1983) presented the case of a 59-year-old man with a
30-year history of a limb-girdle muscular dystrophy due to a presumably
allelic form of this disease. Symptoms began at age 29 years with
progressive difficulty walking up stairs. He showed hyperlordotic
posture, waddling gait, and proximal limb weakness which was greater in
the arms than the legs.

DIAGNOSIS

Shin et al. (1988) demonstrated that the diagnosis of both homozygotes
and heterozygotes can be made on the basis of the study of branching
enzyme activity in erythrocytes. Brown and Brown (1989) described
successful prenatal testing for GSD IV based on levels of branching
enzyme activity in cultured amniotic fluid cells and cultured chorionic
villi.

CLINICAL MANAGEMENT

Selby et al. (1991) reported liver transplantation in 7 boys, including
2 sets of brothers. Two of the 7 died 7 and 36 days after liver
transplantation, from bowel perforation and thrombosis of the hepatic
artery, respectively. The 5 other recipients were healthy and had normal
liver function 16 to 73 months after transplantation. The longest
survival was 73 months in a patient who received a transplant at the age
of 31 months. As pointed out by Howell (1991), some would have predicted
that although the liver failure would be reversed by successful
transplantation, progressive and probably fatal myopathy,
cardiomyopathy, or encephalopathy would develop. However, the experience
of Selby et al. (1991) showed that that was not the case; indeed, the
patients remained healthy and the accumulations of glycogen in the heart
and muscle at the time of liver transplantation seemed to diminish.
Starzl et al. (1993) likewise reported 2 patients with GSD IV in whom
cardiac deposits of amylopectin were dramatically reduced after liver
transplantation. They also reported a striking reduction in lymph node
deposits of glucocerebrosidase in patients with Gaucher disease (230800)
after transplantation. They concluded that systemic microchimerism
occurs after liver allotransplantation and can ameliorate pancellular
enzyme deficiencies.

MOLECULAR GENETICS

Bao et al. (1996) found 2 missense mutations (607839.0004, 607839.0005)
and 1 nonsense mutation (607839.0006) in the GBE gene in 2 patients with
the classic hepatic form of GSD IV. Transient expression experiments
showed that these mutations inactivated glycogen branching enzyme
activity. In a patient with the nonprogressive hepatic form of GSD IV,
they identified compound heterozygosity for 2 GBE1 mutations; one of
these resulted in complete loss of GBE activity (607839.0003), whereas
the other resulted in loss of approximately 50% of GBE activity
(607839.0002). In a patient with the fatal congenital neuromuscular
form, they identified a 210-bp deletion in the GBE cDNA (607839.0001).
The findings indicated that all 3 forms of GSD IV are caused by
mutations in the same gene and that significant retention of GBE
activity may be the reason for mild disease.

In the patient with fatal perinatal GSD IV reported by Alegria et al.
(1999), Bruno et al. (2004) identified a homozygous 274-bp insertion in
the GBE1 gene (607839.0009).

Burrow et al. (2006) reported a 30-month-old girl with GSD IV who had
stable congenital hypotonia with gross motor delay and severe fibrofatty
replacement of the musculature, but no hepatic or cardiac involvement.
Molecular analysis identified compound heterozygosity for 2 missense
mutations in the GBE1 gene (607839.0015-607839.0016). Burrow et al.
(2006) suggested that the unusually mild phenotype in this patient might
be due to residual enzyme activity.

*FIELD* SA
Bannayan et al. (1976); Greene et al. (1987); Howell et al. (1971);
Levin et al. (1968); Schochet et al. (1970); Sidbury et al. (1962)
*FIELD* RF
1. Alegria, A.; Martins, E.; Dias, M.; Cunha, A.; Cardoso, M. L.;
Maire, I.: Glycogen storage disease type IV presenting as hydrops
fetalis. J. Inherit. Metab. Dis. 22: 330-332, 1999.

2. Andersen, D. H.: Familial cirrhosis of the liver with storage
of abnormal glycogen. Lab. Invest. 5: 11-20, 1956.

3. Assereto, S.; van Diggelen, O. P.; Diogo, L.; Morava, E.; Cassandrini,
D.; Carreira, I.; de Boode, W.-P.; Dilling, J.; Garcia, P.; Henriques,
M.; Rebelo, O.; ter Laak, H.; Minetti, C.; Bruno, C.: Null mutations
and lethal congenital forms of glycogen storage disease type IV. Biochem.
Biophys. Res. Commun. 361: 445-450, 2007.

4. Bannayan, G. A.; Dean, W. J.; Howell, R. R.: Type IV glycogen-storage
disease: light-microscopic and enzymatic study. Am. J. Clin. Path. 66:
702-709, 1976.

5. Bao, Y.; Kishnani, P.; Wu, J.-Y.; Chen, Y.-T.: Hepatic and neuromuscular
forms of glycogen storage disease type IV caused by mutations in the
same glycogen-branching enzyme gene. J. Clin. Invest. 97: 941-948,
1996.

6. Brown, B. I.; Brown, D. H.: Branching enzyme activity of cultured
amniocytes and chorionic villi: prenatal testing for type IV glycogen
storage disease. Am. J. Hum. Genet. 44: 378-381, 1989.

7. Brown, B. I.; Brown, D. H.: Lack of an alpha-1,4-glucan: alpha-1,4-glucan
6-glycosyl transferase in a case of type IV glycogenosis. Proc. Nat.
Acad. Sci. 56: 725-729, 1966.

8. Bruno, C.; Cassandrini, D.; Assereto, S.; Akman, H. O.; Minetti,
C.; Di Mauro, S.: Neuromuscular forms of glycogen branching enzyme
deficiency. Acta Myol. 26: 75-78, 2007.

9. Bruno, C.; van Diggelen, O. P.; Cassandrini, D.; Gimpelev, M.;
Giuffre, B.; Donati, M. A.; Introvini, P.; Alegria, A.; Assereto,
S.; Morandi, L.; Mora, M.; Tonoli, E.; Mascelli, S.; Traverso, M.;
Pasquini, E.; Bado, M.; Vilarinho, L.; van Noort, G.; Mosca, F.; DiMauro,
S.; Zara, F.; Minetti, C.: Clinical and genetic heterogeneity of
branching enzyme deficiency (glycogenosis type IV). Neurology 63:
1053-1058, 2004.

10. Burrow, T. A.; Hopkin, R. J.; Bove, K. E.; Miles, L.; Wong, B.
L.; Choudhary, A.; Bali, D.; Li, S. C.; Chen, Y.-T.: Non-lethal congenital
hypotonia due to glycogen storage disease type IV. Am. J. Med. Genet. 140A:
878-882, 2006.

11. Cox, P. M.; Brueton, L. A.; Murphy, K. W.; Worthington, V. C.;
Bjelogrlic, P.; Lazda, E. J.; Sabire, N. J.; Sewry, C. A.: Early-onset
fetal hydrops and muscle degeneration in siblings due to a novel variant
of type IV glycogenosis. Am. J. Med. Genet. 86: 187-193, 1999.

12. Ferguson, I. T.; Mahon, M.; Cumming, W. J. K.: An adult case
of Andersen's disease--type IV glycogenosis: a clinical, histochemical,
ultrastructural and biochemical study. J. Neurol. Sci. 60: 337-351,
1983.

13. Greene, G. M.; Weldon, D. C.; Ferrans, V. J.; Cheatham, J. P.;
McComb, R. D.; Brown, B. I.; Gumbiner, C. H.; Vanderhoff, J. A.; Itkin,
P. G.; McManus, B. M.: Juvenile polysaccharidosis with cardioskeletal
myopathy. Arch. Path. Lab. Med. 111: 977-982, 1987.

14. Greene, H. L.; Brown, B. I.; McClenathan, D. T.; Agostini, R.
M., Jr.; Taylor, S. R.: A new variant of type IV glycogenosis: deficiency
of branching enzyme activity without apparent progressive liver disease. Hepatology 8:
302-306, 1988.

15. Guerra, A. S.; van Diggelen, O. P.; Carneiro, F.; Tsou, R. M.;
Simoes, S.; Santos, N. T.: A juvenile variant of glycogenosis IV
(Andersen disease). Europ. J. Pediat. 145: 179-181, 1986.

16. Howell, R. R.: Continuing lessons from glycogen storage diseases.
(Editorial) New Eng. J. Med. 324: 55-56, 1991.

17. Howell, R. R.; Kaback, M. M.; Brown, B. I.: Type IV glycogen
storage disease: branching enzyme deficiency in skin fibroblasts and
possible heterozygote detection. J. Pediat. 78: 638-642, 1971.

18. Levin, B.; Burgess, E. A.; Mortimer, P. E.: Glycogen storage
disease type IV, amylopectinosis. Arch. Dis. Child. 43: 548-555,
1968.

19. McConkie-Rosell, A.; Wilson, C.; Piccoli, D. A.; Boyle, J.; DeClue,
T.; Kishnani, P.; Shen, J.-J.; Boney, A.; Brown, B.; Chen, Y. T.:
Clinical and laboratory findings in four patients with the non-progressive
hepatic form of type IV glycogen storage disease. J. Inherit. Metab.
Dis. 19: 51-58, 1996.

20. McMaster, K. R.; Powers, J. M.; Hennigar, G. R., Jr.; Wohltmann,
H. J.; Farr, G. H., Jr.: Nervous system involvement in type IV glycogenosis. Arch.
Path. Lab. Med. 103: 105-111, 1979.

21. Reusche, E.; Aksu, F.; Goebel, H. H.; Shin, Y. S.; Yokota, T.;
Reichmann, H.: A mild juvenile variant of type IV glycogenosis. Brain
Dev. 14: 36-43, 1992.

22. Schochet, S. S., Jr.; McCormick, W. F.; Zellweger, H.: Type IV
glycogenosis (amylopectinosis): light and electron microscopic observations. Arch.
Path. 90: 354-363, 1970.

23. Schroder, J. M.; May, R.; Shin, Y. S.; Sigmund, M.; Nase-Huppmeier,
S.: Juvenile hereditary polyglucosan body disease with complete branching
enzyme deficiency (type IV glycogenosis). Acta Neuropath. 85: 419-430,
1993.

24. Selby, R.; Starzl, T. E.; Yunis, E.; Brown, B. I.; Kendall, R.
S.; Tzakis, A.: Liver transplantation for type IV glycogen storage
disease. New Eng. J. Med. 324: 39-42, 1991.

25. Servidei, S.; Riepe, R.; Langston, C.; Tani, L. Y.; Bricker, J.
T.; Crisp Lindgren, N.; Travers, H.; Armstrong, D.; DiMauro, S.:
Severe cardiopathy in branching enzyme deficiency. J. Pediat. 111:
51-56, 1987.

26. Shin, Y. S.; Steiguber, H.; Klemm, P.; Endres, W.; Schwab, O.;
Wolff, G.: Branching enzyme in erythrocytes: detection of type IV
glycogenosis homozygotes and heterozygotes. J. Inherit. Metab. Dis. 11
(suppl. 2): 252-254, 1988.

27. Sidbury, J. B., Jr.; Mason, J.; Burns, W. B., Jr.; Ruebner, B.
H.: Type IV glycogenosis: report of a case proven by characterization
of glycogen and studied at necropsy. Bull. Johns Hopkins Hosp. 111:
157-181, 1962.

28. Starzl, T. E.; Demetris, A. J.; Trucco, M.; Ricordi, C.; Ildstad,
S.; Terasaki, P. I.; Murase, N.; Kendall, R. S.; Kocova, M.; Rudert,
W. A.; Zeevi, A.; Van Thiel, D.: Chimerism after liver transplantation
for type IV glycogen storage disease and type 1 Gaucher's disease. New
Eng. J. Med. 328: 745-749, 1993.

29. Tang, T. T.; Segura, A. D.; Chen, Y.-T.; Ricci, L. M.; Franciosi,
R. A.; Splaingard, M. L.; Lubinsky, M. S.: Neonatal hypotonia and
cardiomyopathy secondary to type IV glycogenosis. Acta Neuropath. 87:
531-536, 1994.

30. Tay, S. K. H.; Akman, H. O.; Chung, W. K.; Pike, M. G.; Muntoni,
F.; Hays, A. P.; Shanske, S.; Valberg, S. J.; Mickelson, J. R.; Tanji,
K.; DiMauro, S.: Fatal infantile neuromuscular presentation of glycogen
storage disease type IV. Neuromusc. Disord. 14: 253-260, 2004.

31. Zellweger, H.; Mueller, S.; Ionasescu, V.; Schochet, S. S.; McCormick,
W. F.: Glycogenosis. IV. A new cause of infantile hypotonia. J.
Pediat. 80: 842-844, 1972.

*FIELD* CS
INHERITANCE:
Autosomal recessive

GROWTH:
[Other];
Failure to thrive

CARDIOVASCULAR:
[Heart];
Cardiomyopathy (in a subset of patients)

ABDOMEN:
Ascites;
[Liver];
Cirrhosis;
Portal hypertension;
Hepatosplenomegaly;
Liver biopsy shows diffuse interstitial fibrosis;
Enlarged hepatocytes with periodic acid-Schiff-positive, diastase-resistant
inclusions;
Electron microscopy shows fibrillar aggregations typical of amylopectin;
[Gastrointestinal];
Esophageal varices

SKELETAL:
Arthrogryposis multiplex (in perinatal or congenital neuromuscular
forms)

MUSCLE, SOFT TISSUE:
Muscle weakness;
Muscle atrophy

NEUROLOGIC:
[Central nervous system];
Hypotonia;
[Peripheral nervous system];
Decreased to absent deep tendon reflexes

PRENATAL MANIFESTATIONS:
[Movement];
Decreased fetal movement (in perinatal or congenital neuromuscular
forms);
[Amniotic fluid];
Polyhydramnios (in perinatal or congenital neuromuscular forms);
Fetal hydrops (in perinatal or congenital neuromuscular forms)

LABORATORY ABNORMALITIES:
Amylo(1,4 - 1,6) transglucosidase deficiency (brancher enzyme);
Broad tissue deposition of amylopectin-like material;
Normal serum creatine kinase

MISCELLANEOUS:
Extreme clinical heterogeneity;
Classic hepatic form begins in first months of life with hepatic failure
and death by age 5 years;
Nonprogressive hepatic form is less frequent;
Neuromuscular forms can present as perinate, infant, child, or adult;
Allelic disorder to adult polyglucosan body disease (263570)

MOLECULAR BASIS:
Caused by mutation in the glycogen branching enzyme gene (GBE1, 607839.0001)

*FIELD* CN
Cassandra L. Kniffin - updated: 2/17/2005
Kelly A. Przylepa - revised: 9/20/2000

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

*FIELD* ED
joanna: 07/02/2013
joanna: 3/15/2005
ckniffin: 2/17/2005
joanna: 6/11/2003
joanna: 3/18/2002
kayiaros: 9/20/2000

*FIELD* CN
Cassandra L. Kniffin - updated: 2/7/2008
Cassandra L. Kniffin - updated: 9/14/2007
Marla J. F. O'Neill - updated: 8/11/2006
Cassandra L. Kniffin - updated: 2/17/2005
Cassandra L. Kniffin - reorganized: 6/10/2003
Victor A. McKusick - updated: 1/10/2000
Sonja A. Rasmussen - updated: 10/5/1999
Victor A. McKusick - updated: 7/15/1999

*FIELD* CD
Victor A. McKusick: 6/3/1986

*FIELD* ED
carol: 09/06/2013
wwang: 2/21/2008
ckniffin: 2/7/2008
wwang: 9/24/2007
ckniffin: 9/14/2007
carol: 4/17/2007
wwang: 8/17/2006
terry: 8/11/2006
terry: 3/22/2006
tkritzer: 4/14/2005
carol: 3/31/2005
ckniffin: 2/17/2005
terry: 6/25/2004
carol: 6/10/2003
ckniffin: 6/10/2003
ckniffin: 5/30/2003
mcapotos: 1/20/2000
mcapotos: 1/18/2000
terry: 1/10/2000
carol: 10/5/1999
jlewis: 8/3/1999
jlewis: 7/30/1999
terry: 7/15/1999
mark: 3/26/1996
terry: 3/19/1996
terry: 5/13/1994
mimadm: 2/19/1994
carol: 10/4/1993
carol: 9/23/1993
carol: 5/14/1993
carol: 5/7/1993

MIM 263570
*RECORD*
*FIELD* NO
263570
*FIELD* TI
#263570 POLYGLUCOSAN BODY DISEASE, ADULT FORM; APBD
*FIELD* TX
A number sign (#) is used with this entry because adult polyglucosan
read morebody disease is caused by mutation in the glycogen branching enzyme gene
(GBE1; 607839). Mutation in the same gene causes type IV glycogen
storage disease (GSD IV; 232500), an early childhood disorder with
systemic manifestations.

CLINICAL FEATURES

Adult polyglucosan body disease is a late-onset, slowly progressive
disorder affecting the central and peripheral nervous systems. Patients
typically present after age 40 years with a variable combination of
cognitive impairment, pyramidal tetraparesis, peripheral neuropathy, and
neurogenic bladder. Other manifestations include cerebellar dysfunction
and extrapyramidal signs. The pathologic hallmark of APBD is the
widespread accumulation of round, intracellular polyglucosan bodies
throughout the nervous system, which are confined to neuronal and
astrocytic processes (Lossos et al., 1998).

Robitaille et al. (1980) reported 4 patients with a clinically and
histopathologically unusual disorder. Two of them were sibs; in Case 4,
the authors stated that 'she is the sister of Case 3.' Curiously, the
sex in Case 3 was not given explicitly or implicitly. The clinical
manifestations were those of progressive lower and upper motor neuron
deficits, marked sensory loss in the legs, neurogenic bladder, and, in 2
of the 4, dementia. Autopsy in 2 showed a profusion of microscopic
bodies resembling corpora amylacea or Lafora bodies, but restricted to
processes of neurons and astrocytes, rather than being perikaryotic.
Similar but especially large bodies were seen within axons of sural
nerves taken at biopsy from the other 2 patients. In addition to Lafora
disease, polyglucosan bodies occur in type IV glycogenosis, in the
'normal' course of aging, in rats rendered diabetic by alloxan, and in a
form of amyotrophic lateral sclerosis (205250). Cases similar to those
of Robitaille et al. (1980) were reported by Peress et al. (1979) and
Suzuki et al. (1971).

Lossos et al. (1991) described 2 unrelated patients diagnosed by sural
nerve biopsy. Both were offspring of consanguineous marriages. They
presented clinically with late-onset pyramidal tetraparesis, micturition
difficulties, peripheral neuropathy, and mild cognitive impairment.
Magnetic resonance imaging showed extensive white matter abnormalities
in both. Lossos et al. (1991) found that branching enzyme activity in
the polymorphonuclear leukocytes of the patients was about 15% of
control values, whereas their children displayed values of 50 to 60%,
consistent with heterozygous state of an autosomal recessive disorder.

Bruno et al. (1993) analyzed branching enzyme activity in muscle,
peripheral nerve, and leukocytes from 2 Ashkenazi-Jewish patients with
adult polyglucosan body disease and 1 African American and 3 Caucasian
patients with the same clinical and pathologic features. One patient was
a 66-year-old woman with progressive gait disturbance for 13 years and
urinary frequency and mild urgency incontinence for 5 years. She had
signs of peripheral neuropathy. A brother died with the diagnosis of
multiple sclerosis, but autopsy revealed adult polyglucosan body disease
with marked central and peripheral nerve system involvement. A
46-year-old French-Canadian woman had progressive gait disturbance and
urinary incontinence over an 8-year period. Branching enzyme activity
was normal in muscle specimens from all patients. The activity was
markedly decreased in both leukocytes and peripheral nerve specimens of
the 2 Jewish patients, and normal in nerve tissue and leukocytes from
all non-Jewish patients. Bruno et al. (1993) concluded that there is a
deficiency of branching enzyme in a subgroup of patients with APBD, in
their experience of only Ashkenazi-Jewish patients, and that APBD has
more than one biochemical basis. Since the enzyme levels were normal in
muscle, even in the Jewish patients, the defect is tissue-specific.

Rifai et al. (1994) reported the case of a 56-year-old man who presented
with lower-limb stiffness and weakness that had progressed for 15 years.
They found that he had a dementia that affected cortical and subcortical
functions and that the cognitive deficits correlated with MRI findings
of cortical atrophy and white-matter abnormalities.

Lossos et al. (1998) reported 7 patients with APBD from 5 unrelated
Jewish families: 4 were of Ashkenazi origin and 1 descended from both
Ashkenazi and Sephardi ancestors. All patients manifested signs of CNS
and PNS involvement, including gait abnormalities, micturition problems,
paresthesias, and cognitive impairment. Brain MRI showed white matter
abnormalities, and sural nerve biopsies showed intraaxonal polyglucosan
bodies. None of the patients had cardiomyopathy or liver dysfunction.
Leukocyte GBE activity was undetectable in all 7 patients and was
reduced to about 50% in their tested children.

MOLECULAR GENETICS

In 7 Jewish patients with APBD, Lossos et al. (1998) identified
homozygosity for a mutation in the GBE gene (607839.0002). Related
family members who were heterozygous for the mutation had only a partial
biochemical defect, thereby demonstrating dosage effect of the mutant
allele consistent with simple autosomal recessive transmission. The
authors noted that the same mutation had been identified in heterozygous
state in a 20-year-old person with normal liver function, and in
compound heterozygous state in a nonprogressive form of type IV GSD.
They concluded that APBD is a variant of GSD type IV.

In a non-Ashkenazi patient with adult polyglucosan body disease,
Ziemssen et al. (2000) identified compound heterozygosity for mutations
in the GBE1 gene (607839.0004 and 607839.0007) that had previously been
identified in patients with GSD type IV. The patient presented at age 46
years with gait disturbance, urinary urge incontinence, and hearing
loss. She also had spastic tetraparesis, extensor plantar responses, and
impaired sensation in the legs. Sural nerve biopsy showed polyglucosan
bodies, and leukocyte GBE activity was 20% of normal. Each of her 2
clinically unaffected daughters carried one of the mutations and showed
intermediate levels of GBE activity (80% of normal). The findings
confirmed that APBD and GSD IV are allelic disorders.

*FIELD* RF
1. Bruno, C.; Servidei, S.; Shanske, S.; Karpati, G.; Carpenter, S.;
McKee, D.; Barohn, R. J.; Hirano, M.; Rifai, Z.; DiMauro, S.: Glycogen
branching enzyme deficiency in adult polyglucosan body disease. Ann.
Neurol. 33: 88-93, 1993.

2. Lossos, A.; Barash, V.; Soffer, D.; Argov, Z.; Gomori, M.; Ben-Nariah,
Z.; Abramsky, O.; Steiner, I.: Hereditary branching enzyme dysfunction
in adult polyglucosan body disease: a possible metabolic cause in
two patients. Ann. Neurol. 30: 655-662, 1991.

3. Lossos, A.; Meiner, Z.; Barash, V.; Soffer, D.; Schlesinger, I.;
Abramsky, O.; Argov, Z.; Shpitzen, S.; Meiner, V.: Adult polyglucosan
body disease in Ashkenazi Jewish patients carrying the tyr329ser mutation
in the glycogen-branching enzyme gene. Ann. Neurol. 44: 867-872,
1998.

4. Peress, N. S.; DiMauro, S.; Roxburgh, V. A.: Adult polysaccharidosis:
clinicopathological, ultrastructural and biochemical features. Arch.
Neurol. 36: 840-845, 1979.

5. Rifai, Z.; Klitzke, M.; Tawil, R.; Kazee, A. M.; Shanske, S.; DiMauro,
S.; Griggs, R. C.: Dementia of adult polyglucosan body disease: evidence
of cortical and subcortical dysfunction. Arch. Neurol. 51: 90-94,
1994.

6. Robitaille, Y.; Carpenter, S.; Karpati, G.; DiMauro, S.: A distinct
form of adult polyglucosan body disease with massive involvement of
central and peripheral neuronal processes and astrocytes: a report
of four cases and a review of the occurrence of polyglucosan bodies
in other conditions such as Lafora's disease and normal ageing. Brain 103:
315-336, 1980.

7. Suzuki, K.; David, E.; Kutschman, B.: Presenile dementia with
'Lafora-like' intraneuronal inclusions. Arch. Neurol. 25: 69-79,
1971.

8. Ziemssen, F.; Sindern, E.; Schroder, J. M.; Shin, Y. S.; Zange,
J.; Kilimann, M. W.; Malin, J.-P.; Vorgerd, M.: Novel missense mutations
in the glycogen-branching enzyme gene in adult polyglucosan body disease. Ann.
Neurol. 47: 536-540, 2000.

*FIELD* CS
INHERITANCE:
Autosomal recessive

GENITOURINARY:
[Bladder];
Neurogenic bladder;
Micturition difficulties

NEUROLOGIC:
[Central nervous system];
Gait disturbance;
Upper motor neuron signs;
Pyramidal tetraparesis;
Neurogenic bladder;
Cognitive impairment;
White matter abnormalities seen on MRI;
Polyglucosan bodies (round intracellular inclusions) found in neuronal
and astrocytic processes;
[Peripheral nervous system];
Peripheral neuropathy;
Distal sensory impairment;
Paresthesias

LABORATORY ABNORMALITIES:
Decreased or absent glycogen branching enzyme activity

MISCELLANEOUS:
Onset after age 40 years;
Slowly progressive;
Allelic disorder to type IV glycogen storage disease (232500)

MOLECULAR BASIS:
Caused by mutation in the glycogen branching enzyme gene (GBE1, 607839.0002)

*FIELD* CN
Cassandra L. Kniffin - revised: 5/30/2003

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

*FIELD* ED
joanna: 10/03/2013
joanna: 6/26/2003
ckniffin: 5/30/2003

*FIELD* CN
Cassandra L. Kniffin - updated: 7/11/2003
Cassandra L. Kniffin - reorganized: 6/10/2003

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
terry: 11/15/2006
carol: 7/14/2003
ckniffin: 7/11/2003
carol: 6/10/2003
ckniffin: 5/30/2003
mimadm: 4/8/1994
carol: 4/1/1994
carol: 2/24/1993
supermim: 3/17/1992
carol: 12/11/1991
supermim: 3/20/1990

MIM 607839
*RECORD*
*FIELD* NO
607839
*FIELD* TI
*607839 GLYCOGEN BRANCHING ENZYME; GBE1
;;GBE;;
1,4-@ALPHA-GLUCAN BRANCHING ENZYME;;
read moreAMYLO-(1,4 to 1,6) TRANSGLUCOSIDASE;;
AMYLO-(1,4 to 1,6) TRANSGLYCOSYLASE
*FIELD* TX

DESCRIPTION

The GBE1 gene encodes the glycogen branching enzyme (EC 2.4.1.18), which
is involved in glycogen synthesis that catalyzes the transfer of
alpha-1,4-linked glucosyl units from the outer end of a glycogen chain
to an alpha-1,6 position on the same or a neighboring glycogen chain.
Branching of the chains is essential to pack a very large number of
glycosyl units into a relatively soluble spherical molecule.

CLONING

Thon et al. (1993) used functional complementation of the Saccharomyces
cerevisiae glycogen branching enzyme deficiency to isolate human cDNAs
that encode the glycogen branching enzyme. The human and yeast glycogen
branching enzymes were found to have 67% identical amino acid sequence
over a major portion of their length. The full length of the cDNA was
approximately 3 kb. The coding sequence contained 2,106 bp encoding a
702-amino acid protein. The calculated molecular mass of the GBE1
protein, derived from its cDNA sequence, was 80,438 Da.

MAPPING

By Southern blot analysis of DNA derived from human/rodent somatic cell
hybrids, Thon et al. (1993) mapped the GBE1 gene to chromosome 3.

MOLECULAR GENETICS

In 2 patients with the classic hepatic presentation of type IV glycogen
storage disease (GSD IV; 232500), Bao et al. (1996) found 2 missense
mutations (607839.0004, 607839.0005) and 1 nonsense mutation
(607839.0006) in the GBE1 gene. Transient expression experiments showed
that these mutations inactivated glycogen branching enzyme activity. In
a different patient with the nonprogressive hepatic form of GSD IV, Bao
et al. (1996) identified compound heterozygosity for 2 mutations in the
GBE1 gene; 1 of these resulted in complete loss of GBE1 activity
(607839.0003), whereas the other resulted in loss of approximately 50%
of GBE1 activity (607839.0002). In a patient with the fatal neonatal
neuromuscular form of GSD IV, they found a 210-bp deletion in the GBE1
cDNA (607839.0001). The findings indicated that all 3 forms of GSD IV
are caused by mutations in the same gene, and that significant retention
of GBE1 activity may underlie milder forms of the disease.

In 7 Jewish patients with adult polyglucosan body disease (APBD;
263570), Lossos et al. (1998) identified homozygosity for a mutation in
the GBE1 gene (607839.0002). Related family members who were
heterozygous for the mutation had only a partial biochemical defect,
thereby demonstrating dosage effect of the mutant allele consistent with
simple autosomal recessive transmission. The authors noted that the same
mutation had been identified in heterozygous state in a 20-year-old
person with normal liver function, and in compound heterozygous state in
a nonprogressive form of GSD IV. They concluded that APBD represents an
allelic variant of GSD IV.

In a non-Ashkenazi patient with APBD, Ziemssen et al. (2000) identified
compound heterozygosity for the R515C mutation (607839.0004) and the
R524Q mutation (607839.0007) in the GBE1 gene, both of which had been
found in patients with GSD IV. Each of her 2 clinically unaffected
daughters carried one of the mutations and showed intermediate levels of
GBE1 activity (80% of normal). The findings confirmed that APBD and GSD
IV are allelic disorders.

Burrow et al. (2006) reported a 30-month-old girl with GSD IV who had
stable congenital hypotonia, gross motor delay, and severe fibrofatty
replacement of the musculature, but no hepatic or cardiac involvement.
Molecular analysis identified compound heterozygosity for 2 missense
mutations in the GBE1 gene (607839.0015 and 607839.0016).

ANIMAL MODEL

Fyfe et al. (1997) showed that a fatal form of GSD IV in Norwegian
Forest cats, in which striated muscles and the nervous system are
primarily affected, is caused by a 6.1-kb deletion that eliminates exon
12 of the feline GBE1 gene. Ward et al. (2004) showed that a fatal
neonatal disorder closely resembling GSD IV in the American Quarter
horse is caused by a 102C-A transversion in exon 1 of the GBE1 gene,
resulting in a tyr34-to-ter (Y34X) substitution.

Fyfe et al. (2007) further characterized the GBE1 mutation in Norwegian
forest cats and found that affected cats are homozygous for a complex
rearrangement of genomic DNA in GBE1, constituted by a 334-bp insertion
at the site of 6.2-kb deletion that extends from intron 11 to intron 12
(IVS11+1552_IVS12-1339 del6.2kb ins334bp), removing exon 12. Screening
of 402 privately owned Norwegian forest cats revealed 58 carriers and 4
affected cats. Not all of these died in the neonatal period, suggesting
a viable animal model for the studies of pathophysiology and development
of novel therapeutic agents.

*FIELD* AV
.0001
GLYCOGEN STORAGE DISEASE IV, CONGENITAL NEUROMUSCULAR
GBE1, IVSAS, G-A, -1

In a patient with neonatal hypotonia and cardiomyopathy secondary to
type IV glycogen storage disease (232500) reported by Tang et al.
(1994), Bao et al. (1996) found a 210-bp deletion from nucleotide 873 to
1082 of the GBE1 cDNA. This deletion resulted in a loss of 70 amino
acids from the GBE polypeptide (262-331). This deletion, representing
the loss of an exon, was caused by an AG-to-AA mutation at a 3-prime
acceptor splice site, and abolished GBE1 activity.

.0002
GLYCOGEN STORAGE DISEASE IV, NONPROGRESSIVE HEPATIC
ADULT POLYGLUCOSAN BODY DISEASE, INCLUDED
GBE1, TYR329SER

In a Jewish female infant with the nonprogressive hepatic form of GSD IV
(232500), Bao et al. (1996) found 2 missense mutations on separate
alleles of the GBE1 gene: leu224-to-pro (L224P; 607839.0003) and
tyr329-to-ser (Y329S). The L224P mutation resulted in complete loss of
GBE1 activity, whereas the Y329S mutation resulted in loss of
approximately 50% of GBE1 activity. Bao et al. (1996) detected the Y329S
allele in another patient with the nonprogressive form of GSD IV but not
in 35 unrelated controls or in patients with the more severe forms of
GSD IV. The Y329S substitution resulted from an A-to-C transversion at
nucleotide 1076. The second patient with the Y329S allele was 20 years
old at the time of report and had normal liver function.

In 7 Jewish patients with adult polyglucosan body disease (APBD;
263570), Lossos et al. (1998) identified homozygosity for the Y329S
mutation. The authors concluded that despite the very different
phenotypes of APBD and GSD IV, they are allelic disorders.

.0003
GLYCOGEN STORAGE DISEASE IV, NONPROGRESSIVE HEPATIC
GBE1, LEU224PRO

See 607839.0002 and Bao et al. (1996). This mutation resulted in
complete loss of GBE1 activity.

.0004
GLYCOGEN STORAGE DISEASE IV, CLASSIC HEPATIC
ADULT POLYGLUCOSAN BODY DISEASE, INCLUDED
GBE1, ARG515CYS

In an infant with type IV GSD (232500) who presented in progressive
liver cirrhosis and failure and died of liver failure before 4 years of
age, Bao et al. (1996) identified a 1633C-T transition in the GBE1 gene,
resulting in an arg515-to-cys substitution (R515C).

In a non-Ashkenazi patient with adult polyglucosan body disease (APBD;
263570), Ziemssen et al. (2000) identified compound heterozygosity for
the R515C mutation and the R524Q mutation (607839.0007) in the GBE1
gene. The patient presented at age 46 years with gait disturbance,
urinary urge incontinence, and hearing loss. She also had spastic
tetraparesis, extensor plantar responses, and impaired sensation in the
legs. Sural nerve biopsy showed polyglucosan bodies, and leukocyte GBE1
activity was 20% of normal. Each of her 2 clinically unaffected
daughters carried one of the mutations and showed intermediate levels of
GBE1 activity (80% of normal). The findings confirmed that APBD and GSD
IV are allelic disorders.

.0005
GLYCOGEN STORAGE DISEASE IV, CLASSIC HEPATIC
GBE1, PHE257LEU

In a patient with type IV GSD (232500) who presented in early infancy
with progressive liver cirrhosis and failure and subsequently underwent
liver transplantation, Bao et al. (1996) identified an 861T-A
transversion in the GBE1 gene, resulting in a phe257-to-leu substitution
(F257L). The other allele contained a C-to-T transition at nucleotide
1660 (607839.0006) that altered arg524 to a stop codon (R524X).

.0006
GLYCOGEN STORAGE DISEASE IV, CLASSIC HEPATIC
GLYCOGEN STORAGE DISEASE IV, CHILDHOOD NEUROMUSCULAR, INCLUDED
GBE1, ARG524TER

See 607839.0005 and Bao et al. (1996).

In a patient with childhood neuromuscular GSD IV (232500), Bruno et al.
(2004) identified compound heterozygosity for the arg524-to-ter (R524X)
mutation and H628R (607839.0013).

.0007
GLYCOGEN STORAGE DISEASE IV, COMBINED HEPATIC AND MYOPATHIC
ADULT POLYGLUCOSAN BODY DISEASE, INCLUDED
GBE1, ARG524GLN

In a 16-month-old infant with a combination of hepatic and muscular
features of GSD IV (232500), Bruno et al. (1999) identified compound
heterozygosity for a G-to-A transition in the GBE1 gene, resulting in an
arg524-to-gln (R524Q) substitution, while the other allele was not
expressed. The patient was the only child of healthy, unrelated parents.
At birth he presented with severe hypotonia, flexion contractures of
hips, knees, ankles, elbows, and wrists, and neck pterygium. At age 5
months, he was admitted to hospital for surgical correction of
arthrogryposis. At that time, muscle hypotonia, stunted growth,
hepatosplenomegaly, and liver dysfunction were noted. Laboratory
investigations showed increased levels of liver enzymes, while serum
creatine kinase remained normal. Electromyography showed a myopathic
pattern, with pseudomyotonic discharges. The status of the patient at 22
months of age suggested that the liver dysfunction and the myopathy were
static, that respiratory function was not affected, and that there was
no abnormality of the heart or of mental development. In a follow-up
study of the patient reported by Bruno et al. (1999), Bruno et al.
(2004) identified a second GBE1 mutation on the other allele
(607839.0014).

Also see 607839.0004 and Ziemssen et al. (2000).

.0008
GLYCOGEN STORAGE DISEASE IV, CONGENITAL NEUROMUSCULAR
GBE1, 627-BP DEL , EX8-12DEL

In a patient with the fatal congenital neuromuscular form of GSD IV
(232500), Tay et al. (2004) identified a homozygous 627-bp deletion in
the GBE1 gene, resulting in the deletion of exons 8-12. Residual
branching enzyme activity was 0.8% of normal. The parents were related
and had a previous intrauterine death associated with decreased fetal
movements and polyhydramnios. The patient died at 5.5 weeks of age.

.0009
GLYCOGEN STORAGE DISEASE IV, FATAL PERINATAL NEUROMUSCULAR
GBE1, IVS1DS, G-A, +1

In the patient with fatal perinatal GSD IV (232500) reported by Alegria
et al. (1999), Bruno et al. (2004) identified a homozygous G-to-A
transition at the donor splice site of intron 1 of the GBE1 gene,
resulting in a 274-bp insertion, a premature stop codon, and truncation
of the last 654 amino acids, or greater than 90% of the protein. Both
unaffected parents were heterozygous for the mutation. The patient died
at 4 days of age.

.0010
GLYCOGEN STORAGE DISEASE IV, FATAL PERINATAL NEUROMUSCULAR
GBE1, HIS545ARG

In 2 Syrian sibs, born of consanguineous parents, with fatal perinatal
GSD IV (232500) reported by van Noort et al. (1993), Bruno et al. (2004)
identified a homozygous 1634A-G transition in exon 13 of the GBE1 gene,
resulting in a his545-to-arg (H545R) substitution. In a structural model
based on the E. coli protein, the H545R mutation was predicted to alter
the structure of the protein significantly.

.0011
GLYCOGEN STORAGE DISEASE IV, CONGENITAL NEUROMUSCULAR
GBE1, GLU592TER

In 2 sibs with congenital neuromuscular GSD IV (232500), Bruno et al.
(2004) identified compound heterozygosity for 2 mutations in the GBE1
gene: a G-to-T transversion in exon 13, resulting in a glu592-to-ter
(E592X) substitution and a 253-bp deletion between exon 3 and exon 7
(607839.0012). Residual GBE1 activity in fibroblasts was less than 5%.

.0012
GLYCOGEN STORAGE DISEASE IV, CONGENITAL NEUROMUSCULAR
GBE1, 253-BP DEL

See 607839.0011 and Bruno et al. (2004).

.0013
GLYCOGEN STORAGE DISEASE IV, CHILDHOOD NEUROMUSCULAR
GBE1, HIS628ARG

In a patient with childhood neuromuscular GSD IV (232500), Bruno et al.
(2004) identified compound heterozygosity for 2 mutations in the GBE1
gene: an A-to-G transition in exon 14, resulting in a his628-to-arg
(H628R) substitution and R524X (607839.0006). Residual GBE1 activity in
fibroblasts was 15 to 25%.

.0014
GLYCOGEN STORAGE DISEASE IV, COMBINED HEPATIC AND MYOPATHIC
GBE1, 1-BP INS, 38A

In an infant with a combination of hepatic and muscular features of GSD
IV (232500) reported by Bruno et al. (1999), Bruno et al. (2004)
identified compound heterozygosity for 2 mutations in the GBE1 gene: a
1-bp insertion at codon 13 in exon 1 and an R524Q substitution
(607839.0007). Residual GBE1 activity in fibroblasts was 5 to 10%.

.0015
GLYCOGEN STORAGE DISEASE IV, CONGENITAL NEUROMUSCULAR
GBE1, GLN236HIS

In a 30-month-old girl with stable congenital neuromuscular GSD IV
(232500), Burrow et al. (2006) identified compound heterozygosity for a
708G-C transversion and a 784C-T transition in the GBE1 gene, resulting
in a gln236-to-his (Q236H) and an arg262-to-cys (R262C; 607839.0016)
substitution, respectively. Each parent was a carrier of 1 of the
mutations. The authors stated that the patient was unique among patients
with GSD IV, in that she had a stable myopathy and exhibited no cardiac
or hepatic pathology at age 2.5 years.

.0016
GLYCOGEN STORAGE DISEASE IV, CONGENITAL NEUROMUSCULAR
GBE1, ARG262CYS

See 607839.0015 and Burrow et al. (2006).

.0017
GLYCOGEN STORAGE DISEASE IV, CONGENITAL NEUROMUSCULAR
GBE1, IVS5DS, G-C, +5

In a female infant with congenital neuromuscular GSD4 (232500), Assereto
et al. (2007) identified a homozygous G-to-C transversion in intron 5 of
the GBE1 gene (IVS5DS+5G-C), resulting in 2 abnormal mRNA transcripts
lacking exon 5 and exons 5 and 6, respectively, that both led to a
frameshift and premature termination. The pregnancy was complicated by
polyhydramnios and reduced fetal movements, and she was born with severe
hypotonia and flexion contractures. She died at age 4 weeks of
cardiorespiratory failure. Each parent was heterozygous for the
mutation. Assereto et al. (2007) emphasized that null mutations in the
GBE1 gene are associated with a severe, often lethal, phenotype.

.0018
GLYCOGEN STORAGE DISEASE IV, CONGENITAL NEUROMUSCULAR
GBE1, TRP548TER

In a female infant with congenital neuromuscular GSD4 (232500), Assereto
et al. (2007) identified a homozygous 1643G-A transition in exon 13 of
the GBE1 gene, resulting in a trp548-to-ter (W548X) substitution. The
pregnancy was complicated by polyhydramnios and reduced fetal movements.
She was born with severe hypotonia and died at age 12 weeks of
cardiorespiratory failure. Each parent was heterozygous for the
mutation. Assereto et al. (2007) emphasized that null mutations in the
GBE1 gene are associated with a severe, often lethal, phenotype.

*FIELD* RF
1. Alegria, A.; Martins, E.; Dias, M.; Cunha, A.; Cardoso, M. L.;
Maire, I.: Glycogen storage disease type IV presenting as hydrops
fetalis. J. Inherit. Metab. Dis. 22: 330-332, 1999.

2. Assereto, S.; van Diggelen, O. P.; Diogo, L.; Morava, E.; Cassandrini,
D.; Carreira, I.; de Boode, W.-P.; Dilling, J.; Garcia, P.; Henriques,
M.; Rebelo, O.; ter Laak, H.; Minetti, C.; Bruno, C.: Null mutations
and lethal congenital forms of glycogen storage disease type IV. Biochem.
Biophys. Res. Commun. 361: 445-450, 2007.

3. Bao, Y.; Kishnani, P.; Wu, J.-Y.; Chen, Y.-T.: Hepatic and neuromuscular
forms of glycogen storage disease type IV caused by mutations in the
same glycogen-branching enzyme gene. J. Clin. Invest. 97: 941-948,
1996.

4. Bruno, C.; DiRocco, M.; Lamba, L. D.; Bado, M.; Marino, C.; Tsujino,
S.; Shanske, S.; Stella, G.; Minetti, C.; van Diggelen, O. P.; DiMauro,
S.: A novel missense mutation in the glycogen branching enzyme gene
in a child with myopathy and hepatopathy. Neuromusc. Disord. 9:
403-407, 1999.

5. Bruno, C.; van Diggelen, O. P.; Cassandrini, D.; Gimpelev, M.;
Giuffre, B.; Donati, M. A.; Introvini, P.; Alegria, A.; Assereto,
S.; Morandi, L.; Mora, M.; Tonoli, E.; Mascelli, S.; Traverso, M.;
Pasquini, E.; Bado, M.; Vilarinho, L.; van Noort, G.; Mosca, F.; DiMauro,
S.; Zara, F.; Minetti, C.: Clinical and genetic heterogeneity of
branching enzyme deficiency (glycogenosis type IV). Neurology 63:
1053-1058, 2004.

6. Burrow, T. A.; Hopkin, R. J.; Bove, K. E.; Miles, L.; Wong, B.
L.; Choudhary, A.; Bali, D.; Li, S. C.; Chen, Y.-T.: Non-lethal congenital
hypotonia due to glycogen storage disease type IV. Am. J. Med. Genet. 140A:
878-882, 2006.

7. Fyfe, J. C.; Kurzhals, R. L.; Hawkins, M. G.; Wang, P.; Yuhki,
N.; Giger, U.; Van Winkle, T. J.; Haskins, M. E.; Patterson, D. F.;
Henthorn, P. S.: A complex rearrangement in GBE1 causes both perinatal
hypoglycemic collapse and late-juvenile-onset neuromuscular degeneration
in glycogen storage disease type IV of Norwegian forest cats. Molec.
Genet. Metab. 90: 383-392, 2007. Note: Erratum: Molec. Genet. Metab.
104: 423 only, 2011.

8. Fyfe, J. C.; Kurzhals, R. L.; Henthorn, P. S.; Patterson, D. F.
: Feline glycogenosis type IV is caused by a complex rearrangement
deleting 6 kb of the branching enzyme gene and eliminating an exon.
(Abstract) Am. J. Hum. Genet. 61: A251 only, 1997.

9. Lossos, A.; Meiner, Z.; Barash, V.; Soffer, D.; Schlesinger, I.;
Abramsky, O.; Argov, Z.; Shpitzen, S.; Meiner, V.: Adult polyglucosan
body disease in Ashkenazi Jewish patients carrying the tyr329ser mutation
in the glycogen-branching enzyme gene. Ann. Neurol. 44: 867-872,
1998.

10. Tang, T. T.; Segura, A. D.; Chen, Y.-T.; Ricci, L. M.; Franciosi,
R. A.; Splaingard, M. L.; Lubinsky, M. S.: Neonatal hypotonia and
cardiomyopathy secondary to type IV glycogenosis. Acta Neuropath. 87:
531-536, 1994.

11. Tay, S. K. H.; Akman, H. O.; Chung, W. K.; Pike, M. G.; Muntoni,
F.; Hays, A. P.; Shanske, S.; Valberg, S. J.; Mickelson, J. R.; Tanji,
K.; DiMauro, S.: Fatal infantile neuromuscular presentation of glycogen
storage disease type IV. Neuromusc. Disord. 14: 253-260, 2004.

12. Thon, V. J.; Khalil, M.; Cannon, J. F.: Isolation of human glycogen
branching enzyme cDNAs by screening complementation in yeast. J.
Biol. Chem. 268: 7509-7513, 1993.

13. van Noort, G.; Straks, W.; Van Diggelen, O. P.; Hennekam, R. C.
M.: A congenital variant of glycogenosis type IV. Pediat. Path. 13:
685-698, 1993.

14. Ward, T. L.; Valberg, S. J.; Adelson, D. L.; Abbey, C. A.; Binns,
M. M.; Mickelson, J. R.: Glycogen branching enzyme (GBE1) mutation
causing equine glycogen storage disease IV. Mammalian Genome 15:
570-577, 2004.

15. Ziemssen, F.; Sindern, E.; Schroder, J. M.; Shin, Y. S.; Zange,
J.; Kilimann, M. W.; Malin, J.-P.; Vorgerd, M.: Novel missense mutations
in the glycogen-branching enzyme gene in adult polyglucosan body disease. Ann.
Neurol. 47: 536-540, 2000.

*FIELD* CN
Cassandra L. Kniffin - updated: 9/14/2007
Ada Hamosh - updated: 6/14/2007
Marla J. F. O'Neill - updated: 8/11/2006
Victor A. McKusick - updated: 8/23/2004
Cassandra L. Kniffin - updated: 7/11/2003

*FIELD* CD
Cassandra L. Kniffin: 5/30/2003

*FIELD* ED
carol: 09/19/2013
carol: 9/6/2013
terry: 12/21/2012
carol: 8/19/2010
wwang: 9/24/2007
ckniffin: 9/14/2007
alopez: 6/22/2007
terry: 6/14/2007
wwang: 8/17/2006
terry: 8/11/2006
terry: 12/20/2005
terry: 9/27/2005
carol: 3/31/2005
ckniffin: 2/17/2005
tkritzer: 8/31/2004
terry: 8/23/2004
carol: 7/14/2003
ckniffin: 7/11/2003
carol: 6/10/2003
ckniffin: 6/10/2003
carol: 6/10/2003
ckniffin: 5/30/2003