RBCC Red Blood Cell Collection

PANK2 (C20orf48) [Confidence: low (only semi-automatic identification from reviews)]
Pantothenate kinase 2, mitochondrial; hPanK2; 2.7.1.33 (Pantothenic acid kinase 2; Flags: Precursor)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt Q9BZ23
ID PANK2_HUMAN Reviewed; 570 AA.
AC Q9BZ23; B1AK33; B2Z3X0; D3DVZ0; Q5T7I2; Q5T7I4; Q7RTX5; Q8N7Q4;
read moreAC Q8TCR5; Q9BYW5; Q9HAF2;
DT 17-JAN-2003, integrated into UniProtKB/Swiss-Prot.
DT 28-NOV-2006, sequence version 3.
DT 22-JAN-2014, entry version 123.
DE RecName: Full=Pantothenate kinase 2, mitochondrial;
DE Short=hPanK2;
DE EC=2.7.1.33;
DE AltName: Full=Pantothenic acid kinase 2;
DE Flags: Precursor;
GN Name=PANK2; Synonyms=C20orf48;
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] (ISOFORM 1), VARIANT ALA-126, AND
RP SUBCELLULAR LOCATION.
RC TISSUE=Brain;
RX PubMed=12554685; DOI=10.1093/hmg/ddg026;
RA Hoertnagel K., Prokisch H., Meitinger T.;
RT "An isoform of hPANK2, deficient in pantothenate kinase-associated
RT neurodegeneration, localizes to mitochondria.";
RL Hum. Mol. Genet. 12:321-327(2003).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3), AND NUCLEOTIDE
RP SEQUENCE [LARGE SCALE MRNA] OF 106-570 (ISOFORM 1).
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 [GENOMIC DNA], AND VARIANTS PRO-94; GLN-111 AND
RP ALA-126.
RG NIEHS SNPs program;
RL Submitted (MAR-2008) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=11780052; DOI=10.1038/414865a;
RA Deloukas P., Matthews L.H., Ashurst J.L., Burton J., Gilbert J.G.R.,
RA Jones M., Stavrides G., Almeida J.P., Babbage A.K., Bagguley C.L.,
RA Bailey J., Barlow K.F., Bates K.N., Beard L.M., Beare D.M.,
RA Beasley O.P., Bird C.P., Blakey S.E., Bridgeman A.M., Brown A.J.,
RA Buck D., Burrill W.D., Butler A.P., Carder C., Carter N.P.,
RA Chapman J.C., Clamp M., Clark G., Clark L.N., Clark S.Y., Clee C.M.,
RA Clegg S., Cobley V.E., Collier R.E., Connor R.E., Corby N.R.,
RA Coulson A., Coville G.J., Deadman R., Dhami P.D., Dunn M.,
RA Ellington A.G., Frankland J.A., Fraser A., French L., Garner P.,
RA Grafham D.V., Griffiths C., Griffiths M.N.D., Gwilliam R., Hall R.E.,
RA Hammond S., Harley J.L., Heath P.D., Ho S., Holden J.L., Howden P.J.,
RA Huckle E., Hunt A.R., Hunt S.E., Jekosch K., Johnson C.M., Johnson D.,
RA Kay M.P., Kimberley A.M., King A., Knights A., Laird G.K., Lawlor S.,
RA Lehvaeslaiho M.H., Leversha M.A., Lloyd C., Lloyd D.M., Lovell J.D.,
RA Marsh V.L., Martin S.L., McConnachie L.J., McLay K., McMurray A.A.,
RA Milne S.A., Mistry D., Moore M.J.F., Mullikin J.C., Nickerson T.,
RA Oliver K., Parker A., Patel R., Pearce T.A.V., Peck A.I.,
RA Phillimore B.J.C.T., Prathalingam S.R., Plumb R.W., Ramsay H.,
RA Rice C.M., Ross M.T., Scott C.E., Sehra H.K., Shownkeen R., Sims S.,
RA Skuce C.D., Smith M.L., Soderlund C., Steward C.A., Sulston J.E.,
RA Swann R.M., Sycamore N., Taylor R., Tee L., Thomas D.W., Thorpe A.,
RA Tracey A., Tromans A.C., Vaudin M., Wall M., Wallis J.M.,
RA Whitehead S.L., Whittaker P., Willey D.L., Williams L., Williams S.A.,
RA Wilming L., Wray P.W., Hubbard T., Durbin R.M., Bentley D.R., Beck S.,
RA Rogers J.;
RT "The DNA sequence and comparative analysis of human chromosome 20.";
RL Nature 414:865-871(2001).
RN [5]
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 [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 406-570.
RC TISSUE=Brain;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H.,
RA Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K.,
RA Ottenwaelder B., Poustka A., Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [7]
RP IDENTIFICATION, ALTERNATIVE INITIATION AT LEU-111, VARIANTS GLN-111
RP AND ALA-126, VARIANTS NBIA1 VAL-219; ALA-234; TRP-264; CYS-278;
RP VAL-282; CYS-286; ILE-327; PRO-351; SER-355; ILE-404; PRO-413;
RP ASN-471; THR-497; ILE-500; ARG-521 AND MET-528, AND TISSUE
RP SPECIFICITY.
RX PubMed=11479594; DOI=10.1038/ng572;
RA Zhou B., Westaway S.K., Levinson B., Johnson M.A., Gitschier J.,
RA Hayflick S.J.;
RT "A novel pantothenate kinase gene (PANK2) is defective in
RT Hallervorden-Spatz syndrome.";
RL Nat. Genet. 28:345-349(2001).
RN [8]
RP INVOLVEMENT IN HARP.
RX PubMed=12058097;
RA Ching K.H.L., Westaway S.K., Gitschier J., Higgins J.J.,
RA Hayflick S.J.;
RT "HARP syndrome is allelic with pantothenate kinase-associated
RT neurodegeneration.";
RL Neurology 58:1673-1674(2002).
RN [9]
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 [10]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-168; SER-169 AND
RP SER-189, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [11]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-168; SER-169 AND
RP SER-189, AND MASS SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [12]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-189, 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 PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-168 AND SER-189, AND
RP MASS 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 [14]
RP VARIANTS NBIA1 GLY-134; PRO-249; LEU-278; ASP-322; GLY-322; GLN-357;
RP THR-398; LEU-425 DEL; TYR-428; ASN-447; THR-501; VAL-509; ASP-511;
RP TRP-532; PRO-563 AND LEU-570.
RX PubMed=12510040; DOI=10.1056/NEJMoa020817;
RA Hayflick S.J., Westaway S.K., Levinson B., Zhou B., Johnson M.A.,
RA Ching K.H., Gitschier J.;
RT "Genetic, clinical, and radiographic delineation of Hallervorden-Spatz
RT syndrome.";
RL N. Engl. J. Med. 348:33-40(2003).
RN [15]
RP VARIANTS NBIA1 ARG-521 AND LEU-570.
RX PubMed=15834858; DOI=10.1002/mds.20476;
RA Nicholas A.P., Earnst K.S., Marson D.C.;
RT "Atypical Hallervorden-Spatz disease with preserved cognition and
RT obtrusive obsessions and compulsions.";
RL Mov. Disord. 20:880-886(2005).
CC -!- FUNCTION: May be the master regulator of the CoA biosynthesis (By
CC similarity).
CC -!- CATALYTIC ACTIVITY: ATP + (R)-pantothenate = ADP + (R)-4'-
CC phosphopantothenate.
CC -!- ENZYME REGULATION: Regulated by feedback inhibition by CoA and its
CC thioesters.
CC -!- PATHWAY: Cofactor biosynthesis; coenzyme A biosynthesis; CoA from
CC (R)-pantothenate: step 1/5.
CC -!- SUBUNIT: Homodimer (By similarity).
CC -!- INTERACTION:
CC Q9H2U1:DHX36; NbExp=1; IntAct=EBI-1058434, EBI-1047643;
CC Q9BS40:LXN; NbExp=1; IntAct=EBI-1058434, EBI-1044504;
CC Q9H0J4:QRICH2; NbExp=1; IntAct=EBI-1058434, EBI-1053637;
CC O14827:RASGRF2; NbExp=1; IntAct=EBI-1058434, EBI-1055500;
CC P21796:VDAC1; NbExp=1; IntAct=EBI-1058434, EBI-354158;
CC P27348:YWHAQ; NbExp=1; IntAct=EBI-1058434, EBI-359854;
CC -!- SUBCELLULAR LOCATION: Isoform 1: Mitochondrion.
CC -!- SUBCELLULAR LOCATION: Isoform 2: Cytoplasm (Potential).
CC -!- SUBCELLULAR LOCATION: Isoform 3: Cytoplasm (Potential).
CC -!- SUBCELLULAR LOCATION: Isoform 4: Cytoplasm (Potential).
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing, Alternative initiation; Named isoforms=4;
CC Name=1;
CC IsoId=Q9BZ23-1; Sequence=Displayed;
CC Name=3;
CC IsoId=Q9BZ23-2; Sequence=VSP_007424;
CC Name=2;
CC IsoId=Q9BZ23-3; Sequence=VSP_018825;
CC Note=Produced by alternative initiation at Met-124 of isoform 1;
CC Name=4;
CC IsoId=Q9BZ23-4; Sequence=VSP_038494, VSP_038495;
CC Note=May be produced by alternative initiation at Leu-111 of
CC isoform 1. No experimental confirmation available;
CC -!- TISSUE SPECIFICITY: Ubiquitous.
CC -!- DISEASE: Neurodegeneration with brain iron accumulation 1 (NBIA1)
CC [MIM:234200]: Autosomal recessive neurodegenerative disorder
CC associated with iron accumulation in the brain, primarily in the
CC basal ganglia. Clinical manifestations include progressive muscle
CC spasticity, hyperreflexia, muscle rigidity, dystonia, dysarthria,
CC and intellectual deterioration which progresses to severe dementia
CC over several years. It is clinically classified into classic,
CC atypical, and intermediate phenotypes. Classic forms present with
CC onset in first decade, rapid progression, loss of independent
CC ambulation within 15 years. Atypical forms have onset in second
CC decade, slow progression, maintenance of independent ambulation up
CC to 40 years later. Intermediate forms manifest onset in first
CC decade with slow progression or onset in second decade with rapid
CC progression. Patients with early onset tend to also develop
CC pigmentary retinopathy, whereas those with later onset tend to
CC also have speech disorders and psychiatric features. All patients
CC have the 'eye of the tiger' sign on brain MRI. Note=The disease is
CC caused by mutations affecting the gene represented in this entry.
CC -!- DISEASE: Hypoprebetalipoproteinemia, acanthocytosis, retinitis
CC pigmentosa, and pallidal degeneration (HARP) [MIM:607236]: Rare
CC syndrome with many clinical similarities to PKAN. Note=The disease
CC is caused by mutations affecting the gene represented in this
CC entry.
CC -!- MISCELLANEOUS: The HSS syndrome has been proposed to be renamed
CC because of the unethical activities of Julius Hallervorden and
CC Hugo Spatz during world war II.
CC -!- SIMILARITY: Belongs to the type II pantothenate kinase family.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAC05173.1; Type=Erroneous initiation;
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/PANK2";
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/pank2/";
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DR EMBL; AF494409; AAN32907.1; -; mRNA.
DR EMBL; AK021791; BAB13897.1; -; mRNA.
DR EMBL; AK097796; BAC05173.1; ALT_INIT; mRNA.
DR EMBL; EU595875; ACD11492.1; -; Genomic_DNA.
DR EMBL; AL353194; CAI11036.1; -; Genomic_DNA.
DR EMBL; AL031670; CAI11036.1; JOINED; Genomic_DNA.
DR EMBL; AL353194; CAI11037.1; -; Genomic_DNA.
DR EMBL; AL031670; CAI11037.1; JOINED; Genomic_DNA.
DR EMBL; AL031670; CAI22385.1; -; Genomic_DNA.
DR EMBL; AL353194; CAI22385.1; JOINED; Genomic_DNA.
DR EMBL; AL031670; CAI22386.1; -; Genomic_DNA.
DR EMBL; AL353194; CAI22386.1; JOINED; Genomic_DNA.
DR EMBL; CH471133; EAX10478.1; -; Genomic_DNA.
DR EMBL; CH471133; EAX10476.1; -; Genomic_DNA.
DR EMBL; AL713654; CAD28463.1; -; mRNA.
DR EMBL; BK000010; DAA00004.1; -; mRNA.
DR RefSeq; NP_079236.3; NM_024960.4.
DR RefSeq; NP_705902.2; NM_153638.2.
DR RefSeq; NP_705904.1; NM_153640.2.
DR RefSeq; XP_005260893.1; XM_005260836.1.
DR UniGene; Hs.516859; -.
DR ProteinModelPortal; Q9BZ23; -.
DR SMR; Q9BZ23; 208-569.
DR IntAct; Q9BZ23; 1.
DR MINT; MINT-3319143; -.
DR PhosphoSite; Q9BZ23; -.
DR DMDM; 118572682; -.
DR PaxDb; Q9BZ23; -.
DR PRIDE; Q9BZ23; -.
DR Ensembl; ENST00000316562; ENSP00000313377; ENSG00000125779.
DR Ensembl; ENST00000497424; ENSP00000417609; ENSG00000125779.
DR GeneID; 80025; -.
DR KEGG; hsa:80025; -.
DR UCSC; uc002wkc.3; human.
DR CTD; 80025; -.
DR GeneCards; GC20P003869; -.
DR HGNC; HGNC:15894; PANK2.
DR HPA; HPA008440; -.
DR HPA; HPA021795; -.
DR MIM; 234200; phenotype.
DR MIM; 606157; gene.
DR MIM; 607236; phenotype.
DR neXtProt; NX_Q9BZ23; -.
DR Orphanet; 216873; Atypical pantothenate kinase associated neurodegeneration.
DR Orphanet; 216866; Classic pantothenate kinase associated neurodegeneration.
DR PharmGKB; PA38048; -.
DR eggNOG; COG5146; -.
DR HOVERGEN; HBG053495; -.
DR InParanoid; Q9BZ23; -.
DR KO; K09680; -.
DR OMA; NENINRV; -.
DR OrthoDB; EOG7R2BJR; -.
DR BRENDA; 2.7.1.33; 2681.
DR Reactome; REACT_111217; Metabolism.
DR Reactome; REACT_116125; Disease.
DR SABIO-RK; Q9BZ23; -.
DR UniPathway; UPA00241; UER00352.
DR ChiTaRS; PANK2; human.
DR GeneWiki; PANK2_(gene); -.
DR GenomeRNAi; 80025; -.
DR NextBio; 70178; -.
DR PRO; PR:Q9BZ23; -.
DR ArrayExpress; Q9BZ23; -.
DR Bgee; Q9BZ23; -.
DR CleanEx; HS_PANK2; -.
DR Genevestigator; Q9BZ23; -.
DR GO; GO:0005758; C:mitochondrial intermembrane space; TAS:Reactome.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0004594; F:pantothenate kinase activity; IEA:UniProtKB-EC.
DR GO; GO:0008219; P:cell death; IEA:UniProtKB-KW.
DR GO; GO:0015937; P:coenzyme A biosynthetic process; IEA:UniProtKB-UniPathway.
DR GO; GO:0009108; P:coenzyme biosynthetic process; TAS:Reactome.
DR GO; GO:0015939; P:pantothenate metabolic process; TAS:Reactome.
DR InterPro; IPR004567; Type_II_PanK.
DR Pfam; PF03630; Fumble; 1.
DR TIGRFAMs; TIGR00555; panK_eukar; 1.
PE 1: Evidence at protein level;
KW Alternative initiation; Alternative splicing; ATP-binding;
KW Coenzyme A biosynthesis; Complete proteome; Cytoplasm;
KW Disease mutation; Kinase; Mitochondrion; Neurodegeneration;
KW Nucleotide-binding; Phosphoprotein; Polymorphism; Reference proteome;
KW Transferase; Transit peptide.
FT TRANSIT 1 46 Mitochondrion (Potential).
FT CHAIN 47 570 Pantothenate kinase 2, mitochondrial.
FT /FTId=PRO_0000023201.
FT COMPBIAS 236 243 Poly-Glu.
FT BINDING 392 392 Acetyl-CoA (By similarity).
FT BINDING 395 395 Acetyl-CoA (By similarity).
FT BINDING 407 407 Acetyl-CoA (By similarity).
FT MOD_RES 168 168 Phosphoserine.
FT MOD_RES 169 169 Phosphoserine.
FT MOD_RES 189 189 Phosphoserine.
FT VAR_SEQ 1 291 Missing (in isoform 3).
FT /FTId=VSP_007424.
FT VAR_SEQ 1 123 Missing (in isoform 2).
FT /FTId=VSP_018825.
FT VAR_SEQ 1 110 Missing (in isoform 4).
FT /FTId=VSP_038494.
FT VAR_SEQ 111 111 L -> M (in isoform 4).
FT /FTId=VSP_038495.
FT VARIANT 94 94 R -> P (in dbSNP:rs71647827).
FT /FTId=VAR_054484.
FT VARIANT 111 111 L -> Q (in dbSNP:rs71647828).
FT /FTId=VAR_015152.
FT VARIANT 126 126 G -> A (in dbSNP:rs3737084).
FT /FTId=VAR_015153.
FT VARIANT 134 134 E -> G (in NBIA1).
FT /FTId=VAR_060934.
FT VARIANT 219 219 G -> V (in NBIA1; atypical).
FT /FTId=VAR_015154.
FT VARIANT 234 234 T -> A (in NBIA1; atypical).
FT /FTId=VAR_015155.
FT VARIANT 249 249 R -> P (in NBIA1).
FT /FTId=VAR_060935.
FT VARIANT 264 264 R -> W (in NBIA1).
FT /FTId=VAR_015156.
FT VARIANT 278 278 R -> C (in NBIA1; atypical).
FT /FTId=VAR_015157.
FT VARIANT 278 278 R -> L (in NBIA1).
FT /FTId=VAR_060936.
FT VARIANT 282 282 L -> V (in NBIA1).
FT /FTId=VAR_015158.
FT VARIANT 286 286 R -> C (in NBIA1).
FT /FTId=VAR_015159.
FT VARIANT 322 322 E -> D (in NBIA1; atypical).
FT /FTId=VAR_060937.
FT VARIANT 322 322 E -> G (in NBIA1).
FT /FTId=VAR_060938.
FT VARIANT 327 327 T -> I (in NBIA1).
FT /FTId=VAR_015160.
FT VARIANT 351 351 S -> P (in NBIA1; atypical).
FT /FTId=VAR_015161.
FT VARIANT 355 355 N -> S (in NBIA1; atypical).
FT /FTId=VAR_015162.
FT VARIANT 357 357 R -> Q (in NBIA1).
FT /FTId=VAR_060939.
FT VARIANT 398 398 A -> T (in NBIA1).
FT /FTId=VAR_060940.
FT VARIANT 404 404 N -> I (in NBIA1; atypical).
FT /FTId=VAR_015163.
FT VARIANT 413 413 L -> P (in NBIA1).
FT /FTId=VAR_015164.
FT VARIANT 425 425 Missing (in NBIA1).
FT /FTId=VAR_060941.
FT VARIANT 428 428 C -> Y (in NBIA1).
FT /FTId=VAR_060942.
FT VARIANT 447 447 D -> N (in NBIA1).
FT /FTId=VAR_060943.
FT VARIANT 471 471 S -> N (in NBIA1).
FT /FTId=VAR_015165.
FT VARIANT 497 497 I -> T (in NBIA1).
FT /FTId=VAR_015166.
FT VARIANT 500 500 N -> I (in NBIA1).
FT /FTId=VAR_015167.
FT VARIANT 501 501 I -> T (in NBIA1; atypical).
FT /FTId=VAR_060944.
FT VARIANT 509 509 A -> V (in NBIA1).
FT /FTId=VAR_060945.
FT VARIANT 511 511 N -> D (in NBIA1).
FT /FTId=VAR_060946.
FT VARIANT 521 521 G -> R (in NBIA1; classic and atypical
FT forms).
FT /FTId=VAR_015168.
FT VARIANT 528 528 T -> M (in NBIA1; classic and atypical
FT forms).
FT /FTId=VAR_015169.
FT VARIANT 532 532 R -> W (in NBIA1).
FT /FTId=VAR_060947.
FT VARIANT 563 563 L -> P (in NBIA1).
FT /FTId=VAR_060948.
FT VARIANT 570 570 P -> L (in NBIA1; atypical;
FT dbSNP:rs41279408).
FT /FTId=VAR_060949.
FT CONFLICT 460 460 R -> G (in Ref. 2; BAB13897).
FT CONFLICT 475 475 M -> K (in Ref. 2; BAB13897).
SQ SEQUENCE 570 AA; 62681 MW; 9061A60D6CA93BBB CRC64;
MRRLGPFHPR VHWAAPPSLS SGLHRLLFLR GTRIPSSTTL SPPRHDSLSL DGGTVNPPRV
REPTGREAFG PSPASSDWLP ARWRNGRGGR PRARLCSGWT AAEEARRNPT LGGLLGRQRL
LLRMGGGRLG APMERHGRAS ATSVSSAGEQ AAGDPEGRRQ EPLRRRASSA SVPAVGASAE
GTRRDRLGSY SGPTSVSRQR VESLRKKRPL FPWFGLDIGG TLVKLVYFEP KDITAEEEEE
EVESLKSIRK YLTSNVAYGS TGIRDVHLEL KDLTLCGRKG NLHFIRFPTH DMPAFIQMGR
DKNFSSLHTV FCATGGGAYK FEQDFLTIGD LQLCKLDELD CLIKGILYID SVGFNGRSQC
YYFENPADSE KCQKLPFDLK NPYPLLLVNI GSGVSILAVY SKDNYKRVTG TSLGGGTFFG
LCCLLTGCTT FEEALEMASR GDSTKVDKLV RDIYGGDYER FGLPGWAVAS SFGNMMSKEK
REAVSKEDLA RATLITITNN IGSIARMCAL NENINQVVFV GNFLRINTIA MRLLAYALDY
WSKGQLKALF SEHEGYFGAV GALLELLKIP
//

MIM 234200
*RECORD*
*FIELD* NO
234200
*FIELD* TI
#234200 NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 1; NBIA1
;;PANTOTHENATE KINASE-ASSOCIATED NEURODEGENERATION; PKAN;;
read morePKAN NEUROAXONAL DYSTROPHY, JUVENILE-ONSET;;
HALLERVORDEN-SPATZ DISEASE
*FIELD* TX
A number sign (#) is used with this entry because neurodegeneration with
brain iron accumulation-1 (NBIA1), also known as Hallervorden-Spatz
disease, is caused by homozygous or compound heterozygosity mutation in
the pantothenate kinase-2 gene (PANK2; 606157) on chromosome 20p13.

HARP syndrome (607236) is a rare allelic disorder with a less severe
phenotype and the presence of hypobetalipoproteinemia and
acanthocytosis.

DESCRIPTION

Neurodegeneration with brain iron accumulation is a genetically
heterogeneous disorder characterized by progressive iron accumulation in
the basal ganglia and other regions of the brain, resulting in
extrapyramidal movements, such as parkinsonism and dystonia. Age at
onset, severity, and cognitive involvement are variable (review by
Gregory et al., 2009).

PKAN has been classified clinically as 'classic,' 'atypical,' or
'intermediate.' In the classic form, patients present within the first
decade of life with rapidly progressing disease and loss of ambulation
approximately 15 years later. In the atypical form, patients have onset
in the second decade with slow progression and maintain independent
ambulation after 15 years. In the intermediate form, patients have early
onset and slow progression or later onset and rapid progression.
Patients with early onset tend to develop pigmentary retinopathy,
whereas those with later onset tend to have speech disorders and
psychiatric features. All patients have the 'eye of the tiger' sign on
brain MRI (Hayflick et al., 2003; Pellecchia et al., 2005).

Kumar et al. (2006) noted that the 'eye of the tiger' sign is not
pathognomonic for PANK2 mutations. They reported 2 unrelated adult
patients with cognitive dysfunction who had the characteristic sign on
MRI but did not have mutations in the PANK2 gene.

Gregory et al. (2009) provided a detailed review of the different forms
of neurodegeneration with brain iron accumulation.

In addition, some patients with Kufor-Rakeb syndrome (606693), also
known as Parkinson disease-9 (PARK9), have iron deposition in the basal
ganglia.

- Genetic Heterogeneity of Neurodegeneration with Brain Iron
Accumulation

Neurodegeneration with brain iron accumulation is an umbrella term that
encompasses a group of genetically heterogeneous disorders. See also
NBIA2A (256600) and NBIA2B (610217), both caused by mutation in the
PLA2G6 gene (603604); NBIA3 (606159), caused by mutation in the FTL gene
(134790); NBIA4 (614298), caused by mutation in the C19ORF12 gene
(614297); and NBIA5 (300894), caused by mutation in the WDR45 gene
(300526).

See review of Schneider and Bhatia (2012) on syndromes of
neurodegeneration with brain iron accumulation, including Kufor-Rakeb
disease (606693) and aceruloplasminemia (604290).

CLINICAL FEATURES

The original description of this syndrome by Hallervorden and Spatz
(1922) concerned a sibship of 12 in which 5 sisters showed clinically
increasing dysarthria and progressive dementia, and at autopsy brown
discoloration of the globus pallidus and substantia nigra. Familial
cases have been reported by others as well. About 30 cases were reported
by Meyer (1958). Clinically the condition is characterized by
progressive rigidity, first in the lower and later in the upper
extremities. An equinovarus deformity of the foot has been the first
sign in several cases. Involuntary movements of choreic or athetoid type
sometimes precede or accompany rigidity. Both involuntary movements and
rigidity may involve muscles supplied by cranial nerves, resulting in
difficulties in articulation and swallowing. Mental deterioration and
epilepsy occur in some. Onset is in the first or second decade and death
usually occurs before the age of 30 years.

Elejalde et al. (1978) observed 5 affected persons in a kindred and
suggested that the condition originated in central Europe. Elejalde et
al. (1979) provided a clinical and genetic analysis. This disorder
affects the muscular tone and voluntary movements progressively, making
coordinated movements and chewing and swallowing almost impossible.
Mental deterioration, emaciation, severe feeding difficulties, and
visual impairment occur commonly as late manifestations. The mean
survival time after diagnosis was 11.18 years (SD = 7.8). The
dopamine-neuromelanine system may be involved in the basic pathogenesis.
Malmstrom-Groth and Kristensson (1982) reported the cases of 2 second
cousins who developed clinical signs of a progressive extrapyramidal
motor disorder and mental retardation and died at ages 8 and 11 years.
Iron deposits and axonal dystrophy were found in the pallidum. All 5
sibs in the family originally studied by Hallervorden and Spatz (1922)
died before age 25. Jankovic et al. (1985) described a kindred
ascertained through a 68-year-old man who died after 13 years of
progressive dementia, rigidity, bradykinesia, mild tremor, stooped
posture, slow and shuffling gait, dystonia, blepharospasm, apraxia of
eyelid opening, anarthria, aphonia, and incontinence. At autopsy, he had
generalized brain atrophy with large deposits of iron pigment in the
globus pallidus, caudate and substantia nigra. Axonal spheroids were
found in the globus pallidus, substantia nigra, medulla, and spinal
cord. Neurochemical analysis of the brain showed marked loss of dopamine
in the nigral-striated areas with relative preservation of dopamine in
the limbic areas. Of his 4 sibs, 3 were also affected. The youngest, a
sister, had been diagnosed as having Alzheimer disease. The parents,
nonconsanguineous, died accidentally at age 46.

The diagnosis of Hallervorden-Spatz disease has usually been made
postmortem; however, the description of magnetic resonance imaging (MRI)
alterations in the basal ganglia (Littrup and Gebarski, 1985; Tanfani et
al., 1987; Sethi et al., 1988) suggested the possibility of an in vivo
diagnosis. Angelini et al. (1992) presented the clinical and MRI
findings of 11 patients diagnosed as having Hallervorden-Spatz disease.
Generalized dystonia with predominance of oromandibular involvement,
behavioral changes followed by dementia, and retinal degeneration were
present in all the patients. MRI pallidal abnormalities consisted of
decreased signal intensity in T2-weighted images, compatible with iron
deposits, and of a small area of hyperintensity in its internal segment
('eye of the tiger' sign).

Casteels et al. (1994) described an 8-year-old girl who presented with 3
years of visual impairment and bilateral optic atrophy before developing
dystonia and other typical features of Hallervorden-Spatz disease. The
MRI demonstrated extremely low signal intensity of the globus pallitus
and in the zona reticularis of the substantia nigra on the T2-weighted
images. The red nuclei were spared. The authors suggested that a larger
series of patients with Hallervorden-Spatz disease should be studied
ophthalmologically to exclude the coincidental occurrence of optic
atrophy in a patient with otherwise typical Hallervorden-Spatz disease.

Although there is no clinical myopathy associated with
Hallervorden-Spatz disease, Malandrini et al. (1995) found similar
morphologic changes in skeletal muscle in 2 unrelated patients with
typical Hallervorden-Spatz disease. Both of these patients had mild
elevation of serum creatine kinase. Histologic analysis of biopsy
quadriceps muscle demonstrated subsarcolemmal accumulation of myeloid
structures, dense bodies and debris, endomysial macrophage activation,
focal necrosis, and fiber splitting.

Pellecchia et al. (2005) reported 16 patients with PKAN confirmed by
genetic analysis. Clinically, 5 patients had classic disease, 4 patients
had atypical disease, and 4 had intermediate disease; 3 patients could
not be classified. Regardless of clinical type, most patients presented
with gait abnormalities or writing difficulty. Two patients presented
with psychomotor delay, and 2 presented with motor tics and
obsessive-compulsive features similar to Tourette syndrome (137580). The
most common features were corticospinal signs, dysarthria, dystonia, and
rigidity. Three patients had pigmentary retinopathy, and almost 50% of
patients had psychiatric involvement, including hyperactivity and
depression. All patients had the characteristic 'eye of the tiger' sign
on brain MRI.

DIAGNOSIS

- Differential Diagnosis

Using single photon emission computed tomography (SPECT), Cossu et al.
(2005) found normal striatal presynaptic dopamine activity in 2 sibs
with PKAN confirmed by genetic analysis. The authors suggested that
these SPECT findings, in combination with the classic MRI findings in
PKAN, would aid in the differential diagnosis of the disorder.

MAPPING

Using homozygosity mapping in a large Amish family, Taylor et al. (1996,
1996) mapped Hallervorden-Spatz disease to 20p13-p12.3. Analysis of 9
other families from New Zealand, Australia, Spain, and Italy supported
linkage to this region with a total maximum 2-point lod score of 13.75
at theta = 0.0 for 1 polymorphic microsatellite marker. Homozygosity in
the Amish family and recombinant haplotypes in 3 of the other families
suggested that the gene involved is located in a 4-cM interval between
D20S906 and D20S116. Taylor et al. (1996) found locus heterogeneity for
the disorder; one Japanese family did not show linkage to this region,
indicating the existence of another locus for the disorder.

Using linkage analysis of an extended Amish pedigree, Zhou et al. (2001)
narrowed the critical interval on chromosome 20p13 to a 1.4-Mb interval
that contained 21 known or predicted genes.

MOLECULAR GENETICS

In affected members of an Amish family with Hallervorden-Spatz syndrome,
Zhou et al. (2001) identified a homozygous 7-bp deletion (606157.0001)
in the coding sequence of the PANK2 gene. Additional missense and null
mutations in the PANK2 gene were identified in 32 of 38 individuals with
classic Hallervorden-Spatz syndrome. Mutations on both alleles could be
accounted for in 22 of these 32 individuals. DNA from individuals with
atypical PKAN also demonstrated missense mutations in PANK2. These
individuals have later onset, and their diverse phenotypes include
early-onset Parkinson disease, severe intermittent dystonia, stuttering
with palilalia or facial tics with repetitive hair caressing; all had
evidence of increased basal ganglia iron. One consanguineous family with
pigmentary retinopathy and late-onset dystonia but without radiographic
evidence of brain iron accumulation even into their thirties carried a
homozygous missense mutation (606157.0007). In the group studied, most
mutations were unique, with a notable exception of the gly411-to-arg
mutation (606157.0002), which was present in both classic and atypical
individuals.

In 16 patients with PKAN, Pellecchia et al. (2005) identified 12
mutations in the PANK2 gene, including 5 novel mutations.

GENOTYPE/PHENOTYPE CORRELATIONS

Hayflick et al. (2003) studied 123 patients from 98 families with a
diagnosis of Hallervorden-Spatz syndrome and classified them as having
classic disease or atypical disease. All patients with classic
Hallervorden-Spatz syndrome and one-third of those with atypical disease
had PANK2 mutations. Whereas almost all mutations in patients with
atypical disease led to amino acid changes, those in patients with
classic disease more often resulted in predicted protein truncation.
Patients with atypical disease who had PANK2 mutations were more likely
to have prominent speech-related and psychiatric symptoms than patients
with classic disease or mutation-negative patients with atypical
disease. In all patients with classic or atypical PKAN, T2-weighted MRI
of the brain showed a specific pattern of hyperintensity within the
hypointense medial globus pallidus. This pattern was not seen in any
patients without PANK2 mutations. Predicted levels of pantothenate
kinase-2 protein correlated with the severity of the disease.

Pellecchia et al. (2005) found no genotype/phenotype correlations among
16 patients with PKAN confirmed by genetic analysis.

Hartig et al. (2006) identified homozygous or compound heterozygous
PANK2 mutations in 48 of 72 patients with PKAN. Deletions accounted for
4% of mutated alleles. There was a correlation between predicted
loss-of-function alleles and earlier age at disease onset.

POPULATION GENETICS

In affected members from 4 Dutch families with pantothenate
kinase-associated neurodegeneration, Rump et al. (2005) identified a
3-bp deletion in the PANK2 gene (606157.0014). Haplotype analysis
suggested a founder effect that arose in Friesland, a northern province
of the Netherlands, at the beginning of the ninth century, approximately
38 generations ago. Rump et al. (2005) provided a brief history of the
geographic isolation of the region.

ANIMAL MODEL

Kuo et al. (2005) generated a mouse knockout of the murine Pank2 gene.
Homozygous null mice gradually developed retinal degeneration with
progressive photoreceptor decline, significantly lower scotopic a- and
b-wave amplitudes, decreased cell number and disruption of the outer
segment, and reduced pupillary constriction response. Homozygous male
mutants were infertile due to azoospermia, a condition that was not
appreciated in affected humans. In contrast to the human, homozygous
null mice exhibited no basal ganglia changes or dystonia. By
immunohistochemistry, Pank2 was localized to mitochondria in both retina
and spermatozoa.

HISTORY

Julius Hallervorden (1882-1965), whose name, with that of Hugo Spatz, is
linked to this disorder, made important contributions to neurologic
science (Richardson, 1990). However, as detailed by Shevell (1992), his
active involvement in a euthanasia program in Germany during World War
II raises serious questions about the moral obligations of medical
science. Muller-Hill (1987) reviewed much of this information in his
'Murderous Science.' No euthanasia law was ever enacted in the Third
Reich. Rather, physicians were empowered to carry out 'mercy killings'
but were never obliged to do so. There was never a direct order to
participate, and refusal to cooperate did not result in legal action or
professional setback. Active opponents were many and included such
prominent physicians as Creutzfeldt, another neuropathologist for whom
Creutzfeldt-Jakob disease (123400) is named. Hallervorden's enthusiastic
encouragement of the killings and the other aspects that led to
dehumanization of both the victims and the participants was detailed by
Shevell (1992). In responding to the article by Shevell (1992), several
authors (e.g., Gordon, 1993) suggested that Hallervorden's name should
be removed from this disorder. Shevell (1992) suggested that the disease
might be called 'Martha-Alma disease' for the 2 unfortunate sisters
whose brains were first dissected in the original description of the
condition (Hallervorden and Spatz, 1922). Zhou et al. (2001) suggested
that this disorder be referred to as 'pantothenate kinase-associated
neurodegeneration' to avoid the objectionable eponym and to reflect the
etiology of the disorder.

Shevell (2003) reviewed the unhappy history of Adolf Hitler's 'Aktion
T-4' program, which resulted in the deaths of 70,273 individuals 'judged
to be incurably ill' and provided Hallervorden with his study material.

*FIELD* RF
1. Angelini, L.; Nardocci, N.; Rumi, V.; Zorzi, C.; Strada, L.; Savoiardo,
M.: Hallervorden-Spatz disease: clinical and MRI study of 11 cases
diagnosed in life. J. Neurol. 239: 417-425, 1992.

2. Casteels, I.; Spileers, W.; Swinnen, T.; Demaerel, Ph.; Silberstein,
J.; Casaer, P.; Missotten, L.: Optic atrophy as the presenting sign
in Hallervorden-Spatz syndrome. Neuropediatrics 25: 265-267, 1994.

3. Cossu, G.; Cella, C.; Melis, M.; Antonini, A.; Floris, G. L.; Ruffini,
L.; Spissu, A.: [123-I]FP-CIT SPECT findings in two patients with
Hallervorden-Spatz disease with homozygous mutation in PANK2 gene. Neurology 64:
167-168, 2005.

4. Elejalde, B. R.; de Elejalde, M. M. J.; Lopez, F.: Hallervorden-Spatz
disease. Clin. Genet. 16: 1-18, 1979.

5. Elejalde, B. R.; Elejalde, M. M.; SanJuan, R.; Lopez, F.: Genetic
and nosologic considerations in Hallervorden-Spatz disease. (Abstract) Clin.
Genet. 30: 50A, 1978.

6. Gordon, J.: Julius Hallervorden. (Letter) Neurology 43: 1452,
1993.

7. Gregory, A.; Polster, B. J.; Hayflick, S. J.: Clinical and genetic
delineation of neurodegeneration with brain iron accumulation. J.
Med. Genet. 46: 73-80, 2009.

8. Hallervorden, J.; Spatz, H.: Eigenartige Erkrankung im extrapyramidalen
System mit besonderer Beteiligung des Globus pallidus und der Substantia
nigra.: Ein Beitrag zu den Beziehungen zwischen diesen beiden Zentren. Z.
Ges. Neurol. Psychiat. 79: 254-302, 1922.

9. Hartig, M. B.; Hortnagel, K.; Garavaglia, B.; Zorzi, G.; Kmiec,
T.; Klopstock, T.; Rostasy, K.; Svetel, M.; Kostic, V. S.; Schuelke,
M.; Botz, E.; Weindl, A.; Novakovic, I.; Nardocci, N.; Prokisch, H.;
Meitinger, T.: Genotypic and phenotypic spectrum of PANK2 mutations
in patients with neurodegeneration with brain iron accumulation. Ann.
Neurol. 59: 248-256, 2006.

10. Hayflick, S. J.; Westaway, S. K.; Levinson, B.; Zhou, B.; Johnson,
M. A.; Ching, K. H. L.; Gitschier, J.: Genetic, clinical, and radiographic
delineation of Hallervorden-Spatz syndrome. New Eng. J. Med. 348:
33-40, 2003.

11. Jankovic, J.; Kirkpatrick, J. B.; Blomquist, K. A.; Langlais,
P. J.; Bird, E. D.: Late-onset Hallervorden-Spatz disease presenting
as familial parkinsonism. Neurology 35: 227-234, 1985.

12. Kumar, N.; Boes, C. J.; Babovic-Vuksanovic, D.; Boeve, B. F.:
The 'eye-of-the-tiger' sign is not pathognomonic of the PANK2 mutation. Arch.
Neurol. 63: 292-293, 2006.

13. Kuo, Y.-M.; Duncan, J. L.; Westaway, S. K.; Yang, H.; Nune, G.;
Xu, E. Y.; Hayflick, S. J.; Gitschier, J.: Deficiency of pantothenate
kinase 2 (Pank2) in mice leads to retinal degeneration and azoospermia. Hum.
Molec. Genet. 14: 49-57, 2005.

14. Littrup, P. J.; Gebarski, S. S.: MR imaging of Hallervorden-Spatz
disease. J. Comput. Assist. Tomogr. 9: 491-493, 1985.

15. Malandrini, A.; Bonuccelli, U.; Parrotta, E.; Ceravolo, R.; Berti,
O.; Guazzi, G. C.: Myopathic involvement in two cases of Hallervorden-Spatz
disease. Brain Dev. 17: 286-290, 1995.

16. Malmstrom-Groth, A. G.; Kristensson, K.: Neuroaxonal dystrophy
in childhood: report of two second cousins with Hallervorden-Spatz
disease, and a case of Seitelberger's disease. Acta Paediat. Scand. 71:
1045-1049, 1982.

17. Meyer, A.: The Hallervorden-Spatz syndrome.In: Greenfield, J.
G. (ed.): Neuropathology. London: Edward Arnold Ltd. (pub.)
1958. P. 525ff.

18. Muller-Hill, B.: Murderous Science: Elimination by Scientific
Selection of Jews, Gypsies, and Others, Germany 1933-1945 (Fraser,
G., transl.). Oxford, UK: Oxford Univ. Press , 1987.

19. Pellecchia, M. T.; Valente, E. M.; Cif, L.; Salvi, S.; Albanese,
A.; Scarano, V.; Bonuccelli, U.; Bentivoglio, A. R.; D'Amico, A.;
Marelli, C.; Di Giorgio, A.; Coubes, P.; Barone, P.; Dallapiccola,
B.: The diverse phenotype and genotype of pantothenate kinase-associated
neurodegeneration. Neurology 64: 1810-1812, 2005.

20. Richardson, E. P.: Julius Hallervorden.In: Ashwal S.(ed.): The
Founders of Child Neurology. San Francisco: Norman Publishing
1990. Pp. 506-512.

21. Rump, P.; Lemmink, H. H.; Verschuuren-Bemelmans, C. C.; Grootscholten,
P. M.; Fock, J. M.; Hayflick, S. J.; Westaway, S. K.; Vos, Y. J.;
van Essen, A. J.: A novel 3-bp deletion in the PANK2 gene of Dutch
patients with pantothenate kinase-associated neurodegeneration: evidence
for a founder effect. Neurogenetics 6: 201-207, 2005.

22. Schneider, S. A.; Bhatia, K. P.: Syndromes of neurodegeneration
with brain iron accumulation. Semin. Pediatr. Neurol. 19: 57-66,
2012.

23. Sethi, K. D.; Adams, R. J.; Loring, D. W.; El Gammal, T.: Hallervorden-Spatz
syndrome: clinical and magnetic resonance imaging correlations. Ann.
Neurol. 24: 692-694, 1988.

24. Shevell, M.: Racial hygiene, active euthanasia, and Julius Hallervorden. Neurology 42:
2214-2219, 1992.

25. Shevell, M.: Hallervorden and history. New Eng. J. Med. 348:
3-4, 2003.

26. Tanfani, G.; Mascalchi, M.; Dal Pozzo, G. C.; Taverni, N.; Saia,
A.; Trevisan, C.: MR imaging in a case of Hallervorden-Spatz disease. J.
Comput. Assist. Tomogr. 11: 1057-1058, 1987.

27. Taylor, T. D.; Kramer, P.; Litt, M.; Hayflick, S. J.: Homozygosity
mapping of Hallervorden-Spatz disease to chromosome 20p12.3-p13. Am.
J. Hum. Genet. 59 (suppl.): A18 only, 1996.

28. Taylor, T. D.; Litt, M.; Kramer, P.; Pandolfo, M.; Angelini, L.;
Nardocci, N.; Davis, S.; Pineda, M.; Hattori, H.; Flett, P. J.; Cilio,
M. R.; Bertini, E.; Hayflick, S. J.: Homozygosity mapping of Hallervorden-Spatz
syndrome to chromosome 20p12.3-p13. Nature Genet. 14: 479-481, 1996.
Note: Erratum: Nature Genet. 16: 109 only, 1997.

29. Zhou, B.; Westaway, S. K.; Levinson, B.; Johnson, M. A.; Gitschier,
J.; Hayflick, S. J.: A novel pantothenate kinase gene (PANK2) is
defective in Hallervorden-Spatz syndrome. Nature Genet. 28: 345-349,
2001.

*FIELD* CS
INHERITANCE:
Autosomal recessive

HEAD AND NECK:
[Face];
Facial grimacing;
[Eyes];
Pigmentary retinopathy (more common in classic disease);
Retinal degeneration;
Optic atrophy;
Blepharospasm;
Apraxia of eyelid opening

ABDOMEN:
[Gastrointestinal];
Feeding difficulties;
Dysphagia

GENITOURINARY:
[Bladder];
Incontinence

SKELETAL:
[Feet];
Foot deformity

SKIN, NAILS, HAIR:
[Skin];
Skin pigmentation

MUSCLE, SOFT TISSUE:
Decreased muscle mass;
Myopathic changes on pathology

NEUROLOGIC:
[Central nervous system];
Psychomotor delay;
Extrapyramidal syndrome;
Involuntary movements;
Gait abnormalities;
Walking on toes;
Corticospinal signs (87% of patients in 1 report);
Ataxia;
Choreoathetosis;
Dystonia;
Motor 'tics';
Difficulty writing;
Rigidity;
Parkinsonism;
Orofacial dyskinesia;
Akinesia;
Spasticity;
Stiffness;
Tremor;
Dysarthria;
Speech abnormalities (palilalia);
Cognitive decline;
Dementia, progressive;
Generalized brain atrophy;
Neuroaxonal degeneration in the brain;
Axonal swelling or thickening in the CNS;
Axonal 'spheroid' inclusions in the CNS;
Iron deposits in the globus pallidus, caudate, and substantia nigra;
MRI shows decreased signal intensity in the pallidal nuclei with central
hyperintensity ('eye of the tiger' sign);
[Behavioral/psychiatric manifestations];
Psychiatric abnormalities (more common in patients with atypical disease
and slow progression);
Obsessive-compulsive trait;
Depression;
Hyperactivity;
Behavioral problems

VOICE:
Dysphonia

MISCELLANEOUS:
Clinically classified into classic, atypical, and intermediate phenotypes;
Classic: onset in first decade, rapid progression, loss of independent
ambulation within 15 years;
Atypical: onset in second decade, slow progression, maintenance of
independent ambulation up to 40 years later;
Intermediate: onset in first decade with slow progression or onset
in second decade with rapid progression;
Allelic to the less severe HARP syndrome (607236), which is distinguished
by the presence of hypobetalipoproteinemia and acanthocytosis;
Similar to infantile neuroaxonal dystrophy (INAD, 256600)

MOLECULAR BASIS:
Caused by mutation in the pantothenate kinase-2 gene (PANK2, 607157.0001)

*FIELD* CN
Cassandra L. Kniffin - updated: 8/16/2005
Cassandra L. Kniffin - updated: 2/22/2005
Cassandra L. Kniffin - revised: 1/16/2003

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

*FIELD* ED
joanna: 07/02/2013
ckniffin: 4/13/2010
terry: 2/12/2009
joanna: 9/14/2005
ckniffin: 8/16/2005
joanna: 4/21/2005
ckniffin: 2/22/2005
ckniffin: 1/21/2003
joanna: 1/16/2003
ckniffin: 1/16/2003

*FIELD* CN
Cassandra L. Kniffin - updated: 3/26/2009
George E. Tiller - updated: 10/31/2007
Cassandra L. Kniffin - updated: 7/17/2006
Cassandra L. Kniffin - updated: 4/11/2006
Cassandra L. Kniffin - updated: 3/2/2006
Cassandra L. Kniffin - updated: 8/16/2005
Cassandra L. Kniffin - updated: 6/9/2005
Victor A. McKusick - updated: 1/24/2003
Victor A. McKusick - updated: 9/3/2002
Ada Hamosh - updated: 7/26/2001
Orest Hurko - updated: 2/5/1996
Orest Hurko - updated: 9/24/1995

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

*FIELD* ED
carol: 04/16/2013
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warfield: 3/8/1994
mimadm: 2/19/1994
carol: 12/1/1992

MIM 606157
*RECORD*
*FIELD* NO
606157
*FIELD* TI
*606157 PANTOTHENATE KINASE 2; PANK2
*FIELD* TX

DESCRIPTION

Pantothenate kinase (EC 2.7.2.33) is an essential regulatory enzyme in
read moreCoA biosynthesis, catalyzing the cytosolic phosphorylation of
pantothenate (vitamin B5), N-pantothenoylcysteine, and pantetheine. CoA
is the major acyl carrier, playing a central role in intermediary and
fatty acid metabolism. In both yeast and fly, each with only 1
pantothenate kinase gene, the null mutant is inviable (summary by Zhou
et al., 2001).

CLONING

Using linkage analysis of an extended Amish pedigree, Taylor et al.
(1996) defined an interval on 20p13 that contains the gene mutant in
Hallervorden-Spatz disease, now known as neurodegeneration with brain
iron accumulation-1 (NBIA1; 234200). Zhou et al. (2001) narrowed the
critical region for the disorder by genotyping polymorphic
microsatellite markers in affected families. Analysis of candidate genes
in this 1.4-Mb region led to the identification in the index family of a
7-bp deletion in the coding sequence of a gene with homology to murine
pantothenate kinase-1. PANK2 is a member of a family of eukaryotic genes
consisting of a group of 6 exons that encode homologous core proteins,
preceded by a series of alternate initiating exons, some of which encode
unique N-terminal peptides. By 5-prime RACE and EST analysis, Zhou et
al. (2001) found evidence for at least 5 initiating exons for PANK2, but
only 1 of these, exon 1C, has an open reading frame with potential
initiation codons that splices in-frame to exon 2. Zhou et al. (2001)
found a sequence similar to that of human PANK2 in mouse, with homology
in the derived amino acid sequence extending to the leucine codon at
nucleotide 31 but diverging 5-prime of it. There is precedence for the
use of a leucine initiating codon in humans, which is probably read by a
methionine tRNA. The leucine codon is flanked by a reasonable initiation
consensus sequence. Zhou et al. (2001) also noted the presence of a
stem-loop structure 14 nucleotides downstream from this leucine, the
location of which has been shown to enhance translation initiation at
nonconserved AUG and non-AUG initiation codons. The mouse stem-loop
sequence is nearly identical, with only 3 nucleotide changes, 2 in the
postulated loop of the stem loop and 1 that changes a GC to a GU
basepair, which implies structural conservation. Because of this strong
conservation, Zhou et al. (2001) proposed that the CUG may serve as an
alternative initiation codon for translation in addition to one of the
methionine codons downstream. There is also a 22-bp palindrome at the
junction of spliced exons 1C and 2. This sequence may form a hairpin
structure and thus explain why most PANK2 ESTs terminate just 3-prime of
the palindrome. Zhou et al. (2001) speculated that this sequence may
serve a regulatory function. PANK2 is ubiquitously expressed, including
in retina and infant basal ganglia. Zhou et al. (2001) provided evidence
for pantothenic kinase activity in PANK2 by showing that the human gene
PANK2 can rescue the temperature-sensitive E. coli pantothenate kinase
mutant.

GENE STRUCTURE

Hortnagel et al. (2003) determined the exon-intron structure of the
human PANK2 gene and identified 2 alternatively used first exons. The
resulting transcripts encode distinct isoforms of PANK2, one of which
carries an N-terminal extension with a predicted mitochondrial targeting
signal. An in vitro import assay and in vivo immunolocalization
experiments demonstrated a mitochondrial localization of this isoform.
The authors concluded that the symptoms observed in pantothenate
kinase-associated neurodegeneration (234200) may be caused by a
deficiency of the mitochondrial isoform; they further postulated the
existence of a complete intramitochondrial pathway for de novo synthesis
of coenzyme A.

MOLECULAR GENETICS

Zhou et al. (2001) identified 3 nonsense mutations in exon 1C of the
PANK2 gene in affected individuals with classic Hallervorden-Spatz
disease (234200), also known as neurodegeneration with brain iron
accumulation-1 (NBIA1) or pantothenate kinase-associated
neurodegeneration (PKAN), but not in controls.

In the original patient with HARP syndrome (607236) reported by Higgins
et al. (1992), Ching et al. (2002) identified homozygosity for a
mutation in the PANK2 gene (606157.0011). HARP syndrome shares many
clinical and radiographic features with PKAN, but is distinguished by a
specific lipoprotein abnormality. The mutation identified by Ching et
al. (2002) confirmed that HARP syndrome is part of the PKAN disease
spectrum.

Hayflick et al. (2003) performed clinical assessment and mutation screen
of the PANK2 gene on 123 patients from 98 families with a diagnosis of
Hallervorden-Spatz syndrome, classified on the basis of clinical
assessment as having classic disease (characterized by early onset with
rapid progression) or atypical disease (later onset with slow
progression). PANK2 mutations were found in 66 of the 98 families. Of 49
families whose members had classic disease, all had mutations in PANK2.
Of 49 families whose members had atypical disease, mutations were found
in 17 (35%). Whereas almost all mutations in patients with atypical
disease led to amino acid changes, those in patients with classic
disease more often resulted in predicted protein truncation. Patients
with atypical disease who had PANK2 mutations were more likely to have
prominent speech-related and psychiatric symptoms than patients with
classic disease or mutation-negative patients with atypical disease. In
all patients with pantothenate kinase-associated neurodegeneration,
whether classic or atypical, T2-weighted MRI of the brain showed a
specific pattern of hyperintensity within the hypointense medial globus
pallidus. This pattern was not seen in any patients without mutations.
Predicted levels of pantothenate kinase-2 protein correlated with the
severity of the disease.

In the 66 families with mutations in the PANK2 gene studied by Hayflick
et al. (2003), 2 PANK2 mutations, both of them missense mutations,
accounted for one-third of the disease alleles, G411R (606157.0002) and
T418M (606157.0010). G411R constituted 31 disease-related alleles in 27
families. Eighty-one percent of the 27 families with the G411R mutation
were of European descent. In 6 families (4 with classic disease and 2
with atypical disease), the G411R mutation was found on one chromosome
and no mutation was identified on the other. Families with only 1
identified mutation were not distinguishable from those with 2. Some of
these mutations were undetectable with the screening method used, e.g.,
promoter mutations. Six of the 9 families with a single mutant allele
had only the allele with the G411R mutation. This observation is
striking because mutations in both alleles were detected in nearly all
families, and it suggests that G411R may be semidominant, with 1 allele
sufficient to cause disease given certain genetic backgrounds. Against
this hypothesis was the fact that no disease phenotype was observed in
G411R-heterozygous carrier parents of affected persons.

In 16 patients with PKAN, Pellecchia et al. (2005) identified 12
mutations in the PANK2 gene, including 5 novel mutations. They found no
genotype/phenotype correlations.

Hartig et al. (2006) identified homozygous or compound heterozygous
PANK2 mutations in 48 of 72 patients with PKAN. Deletions accounted for
4% of mutated alleles. There was a correlation between predicted
loss-of-function alleles and earlier age at disease onset.

ANIMAL MODEL

Kuo et al. (2005) generated a mouse knockout of the murine Pank2 gene.
Homozygous null mice gradually developed retinal degeneration with
progressive photoreceptor decline, significantly lower scotopic a- and
b-wave amplitudes, decreased cell number and disruption of the outer
segment, and reduced pupillary constriction response. Homozygous male
mutants were infertile due to azoospermia, a condition that was not
appreciated in affected humans with pantothenate kinase-associated
neurodegeneration (234200). In contrast to the human, homozygous null
mice exhibited no basal ganglia changes or dystonia. By
immunohistochemistry, Pank2 was localized to mitochondria in both retina
and spermatozoa.

Drosophila has only 1 PANK gene, fumble (fbl), which encodes several
isoforms of pantothenate kinase, including a long isoform fblL that
localizes to mitochondria and shorter isoforms fblS1 and fblS2 that
localize to the cytosol. Wu et al. (2009) introduced various isoforms of
Drosophila fbl and human PANK2 into flies to study their in vivo
functions. Only mitochondria-targeted FblL or human PANK2 was able to
rescue a hypomorphic fbl(1) mutation, with the rescuing ability
dependent on the expression level of the transgene. Transgenic lines
with low expression of normal fbl or PANK2 displayed similar phenotypes
as PANK2-mutant transgenic flies. These PANK2 mutants all showed reduced
enzyme activity, and phenotype severity correlated with in vitro enzyme
activity. Cytosolic PANK3 (606161) and PANK4 (606162) could partially
rescue all fbl defects except male sterility. The authors concluded that
fbl is the ortholog of human PANK2, and PANK2 is functionally more
potent than PANK3 and PANK4 in vivo. Wu et al. (2009) suggested that
mitochondria-located pantothenate kinase is required to achieve the
maximal enzymatic activity to fulfill the most challenging biologic
tasks such as maintaining male fertility and optimal neuronal function,
and PKAN features are mainly due to the reduction of the total cellular
pantothenate kinase activity in the most susceptible regions.

*FIELD* AV
.0001
NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 1
PANK2, 7-BP DEL, NT627

In an individual with classic pantothenate kinase-associated
neurodegeneration (234200), Zhou et al. (2001) identified a homozygous
7-bp deletion in exon 2 of the PANK2 gene, resulting in a frameshift.

.0002
NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 1
NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 1, ATYPICAL, INCLUDED
PANK2, GLY411ARG

In 10 individuals with classic pantothenate kinase-associated
neurodegeneration (234200), Zhou et al. (2001) identified a homozygous
1261G-A transition in exon 6 of the PANK2 gene, resulting in a
glycine-to-arginine substitution at codon 411 (G411R). The mutation was
also seen in 7 individuals with atypical PKAN.

.0003
NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 1
PANK2, TYR80TER

In an individual with classic pantothenate kinase-associated
neurodegeneration (234200), Zhou et al. (2001) identified a C-to-G
transversion at nucleotide 270 in exon 1C of the PANK2 gene, resulting
in a tyrosine-to-termination substitution at codon 80 (Y80X). This
mutation was found in compound heterozygosity with arg154 to tyr
(606157.0004). In another affected individual, the mutation was found in
homozygosity.

.0004
NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 1
PANK2, ARG154TRP

In an individual with classic pantothenate kinase-associated
neurodegeneration (234200), Zhou et al. (2001) found a C-to-T transition
at nucleotide 490 of the PANK2 gene, resulting in an arg-to-trp
substitution at codon 154 (R154W). This patient was compound
heterozygous for the Y80X mutation (606157.0003).

.0005
NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 1
PANK2, ARG176CYS

In an individual with classic pantothenate kinase-associated
neurodegeneration (234200), Zhou et al. (2001) identified a C-to-T
transition at nucleotide 556 of the PANK2 gene, resulting in an
arg-to-cys substitution at codon 176 (R176C). This individual was a
compound heterozygote for the G411R mutation (606157.0002).

.0006
NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 1
PANK2, SER361ASN

In an individual with classic pantothenate kinase-associated
neurodegeneration (234200) who was compound heterozygous for an R145W
mutation (606157.0004) in the PANK2 gene, Zhou et al. (2001) identified
a G-to-A transition on the other allele, resulting in a ser361-to-asn
(S361N) amino acid substitution.

.0007
NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 1, ATYPICAL
PANK2, SER240PRO

In an individual with atypical pantothenate kinase-associated
neurodegeneration (234200), Zhou et al. (2001) identified a homozygous
mutation, a T-to-C transition at nucleotide 751 of the PANK2 gene,
resulting in a serine-to-proline substitution at codon 240 (S240P).

.0008
NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 1, ATYPICAL
PANK2, THR124ALA

In an individual with atypical pantothenate kinase-associated
neurodegeneration (234200), Zhou et al. (2001) identified an A-to-G
transition at nucleotide 400 of the PANK2 gene, resulting in a
threonine-to-alanine substitution at codon 124 (T124A).

.0009
NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 1, ATYPICAL
PANK2, ARG168CYS

In an individual with atypical pantothenate kinase-associated
neurodegeneration (234200), Zhou et al. (2001) identified a C-to-T
transition at nucleotide 532of the PANK2 gene, resulting in an
arg-to-cys substitution at codon 168 (R168C). This patient was compound
heterozygous for the G411R mutation (606157.0002).

.0010
NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 1
NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 1, ATYPICAL, INCLUDED
PANK2, THR418MET

In individuals with both typical and atypical pantothenate
kinase-associated neurodegeneration (234200), Zhou et al. (2001)
identified a C-to-T transition at nucleotide 1283 of the PANK2 gene,
resulting in a threonine-to-methionine substitution at codon 418
(T418M). This mutation was found in homozygosity in 2 patients with
classical PKAN, and in compound heterozygosity with the G411R mutation
(606157.0002) in an individual with atypical PKAN.

Hayflick et al. (2003) found the T418M mutation on 10 alleles in 6 of 66
families with PANK2 mutations causing Hallervorden-Spatz syndrome.

.0011
HARP SYNDROME
PANK2, ARG371TER

In the patient originally reported by Higgins et al. (1992) with HARP
syndrome (607236), Ching et al. (2002) demonstrated homozygosity for a
C-to-T transition at nucleotide 1111 in exon 5 of the PANK2 gene. The
mutation changed an arginine codon to a stop codon at amino acid 371 and
shortened PANK2 by 89 amino acids. Ching et al. (2002) suspected that
the patient was the offspring of consanguineous parents because they
came from a village of 500 inhabitants. The patient demonstrated severe
spasticity and dystonia from early childhood. At age 10, she was shown
to have pigmentary retinopathy on funduscopic examination and the 'eye
of the tiger' sign on brain MRI. Peripheral blood smear and electron
microscopy demonstrated marked acanthocytosis that was not due to an
intrinsic erythrocyte protein defect. On high-resolution lipoprotein
electrophoresis, she demonstrated absence of the pre-beta fraction and
normal blood levels of cholesterol, triglycerides, high and low density
lipoprotein cholesterol, and apolipoproteins A, B, and E.

.0012
HARP SYNDROME
PANK2, MET327THR

In a patient with HARP syndrome (607236) initially reported by Orrell et
al. (1995), Houlden et al. (2003) identified compound heterozygosity for
mutations in the PANK2 gene: a 980T-C change in exon 4, resulting in a
met327-to-thr (M327T) substitution, and a splice site mutation
(606157.0013). Her unaffected father and 2 of his unaffected brothers
were heterozygous for the M327T mutation.

.0013
HARP SYNDROME
NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 1, INCLUDED
PANK2, IVS4, G-T, -1

In a patient with HARP syndrome (607236) initially reported by Orrell et
al. (1995), Houlden et al. (2003) identified compound heterozygosity for
mutations in the PANK2 gene: a G-to-T transversion at the splice site of
exon 5 (IVS4-1G-T), and M327T (606157.0012). The patient's mother and
sister, both of whom had acanthocytosis and hypoprebetalipoproteinemia
without neurologic abnormalities, were heterozygous for the splice site
mutation. Houlden et al. (2003) noted that the IVS4 mutation had been
reported in 2 patients with classic pantothenate kinase-associated
neurodegeneration (234200) (Hayflick et al., 2003), thus confirming that
the 2 disorders are allelic.

.0014
NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 1
PANK2, 3-BP DEL, 1142GAG

In affected members from 4 Dutch families with pantothenate
kinase-associated neurodegeneration (234200), Rump et al. (2005)
identified a 3-bp deletion (1142delGAG) in the PANK2 gene. The in-frame
deletion is predicted to result in substitution of arg371 and glu372
with a glutamine in the catalytic domain of the protein. Five patients
from 3 families were homozygous for the mutation. The patient from the
fourth family was compound heterozygous for the deletion and a second
mutation (S68X; 606157.0015). Haplotype analysis suggested a founder
effect that arose in Friesland, a northern province of the Netherlands,
at the beginning of the ninth century, approximately 38 generations ago.

.0015
NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 1
PANK2, SER68TER

In a Dutch patient with pantothenate kinase-associated neurodegeneration
(234200), Rump et al. (2005) identified compound heterozygosity for 2
mutations in the PANK2 gene: a 3-bp deletion (606157.0014) and a 233C-A
transversion, resulting in a ser68-to-ter (S68X) substitution. The
patient had a severe form of the disorder and died at age 12 years.

*FIELD* RF
1. Ching, K. H. L.; Westaway, S. K.; Gitschier, J.; Higgins, J. J.;
Hayflick, S. J.: HARP syndrome is allelic with pantothenate kinase-associated
neurodegeneration. Neurology 58: 1673-1674, 2002.

2. Hartig, M. B.; Hortnagel, K.; Garavaglia, B.; Zorzi, G.; Kmiec,
T.; Klopstock, T.; Rostasy, K.; Svetel, M.; Kostic, V. S.; Schuelke,
M.; Botz, E.; Weindl, A.; Novakovic, I.; Nardocci, N.; Prokisch, H.;
Meitinger, T.: Genotypic and phenotypic spectrum of PANK2 mutations
in patients with neurodegeneration with brain iron accumulation. Ann.
Neurol. 59: 248-256, 2006.

3. Hayflick, S. J.; Westaway, S. K.; Levinson, B.; Zhou, B.; Johnson,
M. A.; Ching, K. H. L.; Gitschier, J.: Genetic, clinical, and radiographic
delineation of Hallervorden-Spatz syndrome. New Eng. J. Med. 348:
33-40, 2003.

4. Higgins, J. J.; Patterson, M. C.; Papadopoulos, N. M.; Brady, R.
O.; Pentchev, P. G.; Barton, N. W.: Hypoprebetalipoproteinemia, acanthocytosis,
retinitis pigmentosa, and pallidal degeneration (HARP syndrome). Neurology 42:
194-198, 1992.

5. Hortnagel, K.; Prokisch, H.; Meitinger, T.: An isoform of hPANK2,
deficient in pantothenate kinase-associated neurodegeneration, localizes
to mitochondria. Hum. Molec. Genet. 12: 321-327, 2003.

6. Houlden, H.; Lincoln, S.; Farrer, M.; Cleland, P. G.; Hardy, J.;
Orrell, R. W.: Compound heterozygous PANK2 mutations confirm HARP
and Hallervorden-Spatz syndromes are allelic. Neurology 61: 1423-1426,
2003.

7. Kuo, Y.-M.; Duncan, J. L.; Westaway, S. K.; Yang, H.; Nune, G.;
Xu, E. Y.; Hayflick, S. J.; Gitschier, J.: Deficiency of pantothenate
kinase 2 (Pank2) in mice leads to retinal degeneration and azoospermia. Hum.
Molec. Genet. 14: 49-57, 2005.

8. Orrell, R. W.; Amrolia, P. J.; Heald, A.; Cleland, P. G.; Owen,
J. S.; Morgan-Hughes, J. A.; Harding, A. E.; Marsden, C. D.: Acanthocytosis,
retinitis pigmentosa, and pallidal degeneration: a report of three
patients, including the second reported case with hypoprebetalipoproteinemia
(HARP syndrome). Neurology 45: 487-492, 1995.

9. Pellecchia, M. T.; Valente, E. M.; Cif, L.; Salvi, S.; Albanese,
A.; Scarano, V.; Bonuccelli, U.; Bentivoglio, A. R.; D'Amico, A.;
Marelli, C.; Di Giorgio, A.; Coubes, P.; Barone, P.; Dallapiccola,
B.: The diverse phenotype and genotype of pantothenate kinase-associated
neurodegeneration. Neurology 64: 1810-1812, 2005.

10. Rump, P.; Lemmink, H. H.; Verschuuren-Bemelmans, C. C.; Grootscholten,
P. M.; Fock, J. M.; Hayflick, S. J.; Westaway, S. K.; Vos, Y. J.;
van Essen, A. J.: A novel 3-bp deletion in the PANK2 gene of Dutch
patients with pantothenate kinase-associated neurodegeneration: evidence
for a founder effect. Neurogenetics 6: 201-207, 2005.

11. Taylor, T. D.; Litt, M.; Kramer, P.; Pandolfo, M.; Angelini, L.;
Nardocci, N.; Davis, S.; Pineda, M.; Hattori, H.; Flett, P. J.; Cilio,
M. R.; Bertini, E.; Hayflick, S. J.: Homozygosity mapping of Hallervorden-Spatz
syndrome to chromosome 20p12.3-p13. Nature Genet. 14: 479-481, 1996.
Note: Erratum: Nature Genet. 16: 109 only, 1997.

12. Wu, Z.; Li, C.; Lv, S.; Zhou, B.: Pantothenate kinase-associated
neurodegeneration: insights from a Drosophila model. Hum. Molec.
Genet. 18: 3659-3672, 2009.

13. Zhou, B.; Westaway, S. K.; Levinson, B.; Johnson, M. A.; Gitschier,
J.; Hayflick, S. J.: A novel pantothenate kinase gene (PANK2) is
defective in Hallervorden-Spatz syndrome. Nature Genet. 28: 345-349,
2001.

*FIELD* CN
George E. Tiller - updated: 7/8/2010
George E. Tiller - updated: 10/31/2007
Cassandra L. Kniffin - updated: 4/11/2006
Cassandra L. Kniffin - updated: 3/2/2006
Cassandra L. Kniffin - updated: 8/16/2005
George E. Tiller - updated: 1/3/2005
Cassandra L. Kniffin - updated: 2/3/2004
Victor A. McKusick - updated: 1/24/2003
Victor A. McKusick - updated: 9/3/2002

*FIELD* CD
Ada Hamosh: 7/30/2001

*FIELD* ED
carol: 04/16/2013
terry: 5/25/2012
wwang: 7/22/2010
terry: 7/8/2010
carol: 3/8/2010
carol: 3/1/2010
carol: 2/25/2010
alopez: 11/2/2007
terry: 10/31/2007
wwang: 4/19/2006
ckniffin: 4/11/2006
wwang: 3/14/2006
ckniffin: 3/2/2006
wwang: 8/23/2005
ckniffin: 8/16/2005
alopez: 1/3/2005
tkritzer: 2/6/2004
ckniffin: 2/3/2004
cwells: 11/18/2003
terry: 1/24/2003
alopez: 11/1/2002
carol: 9/18/2002
tkritzer: 9/17/2002
terry: 9/3/2002
alopez: 7/30/2001

MIM 607236
*RECORD*
*FIELD* NO
607236
*FIELD* TI
#607236 HYPOPREBETALIPOPROTEINEMIA, ACANTHOCYTOSIS, RETINITIS PIGMENTOSA,
AND PALLIDAL DEGENERATION
read more;;HARP SYNDROME
*FIELD* TX
A number sign (#) is used with this entry because HARP syndrome
(hypoprebetalipoproteinemia, acanthocytosis, retinitis pigmentosa, and
pallidal degeneration) is caused by mutation in the gene encoding
pantothenate kinase-2 (PANK2; 606157). Only 2 unrelated genetically
confirmed patients have been reported.

Pantothenate kinase-associated neurodegeneration (PKAN, NBIA1; 234200),
also known as Hallervorden-Spatz disease, is a more severe disorder also
caused by mutation in the PANK2 gene.

CLINICAL FEATURES

Higgins et al. (1992) described a woman with the combination of
hyperprebetalipoproteinemia, acanthocytosis, retinitis pigmentosa, and
pallidal degeneration. She had demonstrated severe spasticity and
dystonia since early childhood. At age 10, she was shown on funduscopic
examination to have pigmentary retinopathy and the 'eye of the tiger'
sign on brain MRI. A peripheral blood smear and electron microscopy
demonstrated marked acanthocytosis that was not due to an intrinsic
erythrocyte protein defect. On high-resolution lipoprotein
electrophoresis, she demonstrated absence of the pre-beta fraction, with
normal blood levels of cholesterol, triglycerides, high and low density
lipoprotein cholesterol, and apolipoproteins A, B, and C.

Orrell et al. (1995) described a second case of HARP syndrome in an
18-year-old woman who presented with longstanding intellectual
subnormality, night blindness, and a 2-year history of orobuccolingual
dystonia causing dysarthria and dysphagia. Investigation showed 53%
acanthocytosis and hypoprebetalipoproteinemia, and ERG was typical of
tapetoretinal degeneration. MRI showed the 'eye of the tiger' sign. The
patient's sister and mother had a similar lipid disorder and
acanthocytosis, but no neurologic or retinal disease. The authors noted
that HARP syndrome shares many clinical and radiographic features with
PKAN, including the 'eye of the tiger' sign, but is distinguished by a
specific lipoprotein abnormality.

MOLECULAR GENETICS

Ching et al. (2002) studied the original patient reported by Higgins et
al. (1992) and identified an arg371-to-ter (R371X) mutation in the PANK2
gene (606157.0011). This finding established that HARP is part of the
PKAN disease spectrum.

In a patient with HARP syndrome initially reported by Orrell et al.
(1995), Houlden et al. (2003) identified compound heterozygosity for
mutations in the PANK2 gene: a met327-to-thr substitution (M327T;
606157.0012) and a splice site mutation (606157.0013). The patient's
mother and sister, both of whom had acanthocytosis and
hypoprebetalipoproteinemia without neurologic abnormalities, were
heterozygous for the splice site mutation, whereas her unaffected father
was heterozygous for the M327T mutation.

*FIELD* RF
1. Ching, K. H. L.; Westaway, S. K.; Gitschier, J.; Higgins, J. J.;
Hayflick, S. J.: HARP syndrome is allelic with pantothenate kinase-associated
neurodegeneration. Neurology 58: 1673-1674, 2002.

2. Higgins, J. J.; Patterson, M. C.; Papadopoulos, N. M.; Brady, R.
O.; Pentchev, P. G.; Barton, N. W.: Hypoprebetalipoproteinemia, acanthocytosis,
retinitis pigmentosa, and pallidal degeneration (HARP syndrome). Neurology 42:
194-198, 1992.

3. Houlden, H.; Lincoln, S.; Farrer, M.; Cleland, P. G.; Hardy, J.;
Orrell, R. W.: Compound heterozygous PANK2 mutations confirm HARP
and Hallervorden-Spatz syndromes are allelic. Neurology 61: 1423-1426,
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4. Orrell, R. W.; Amrolia, P. J.; Heald, A.; Cleland, P. G.; Owen,
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(HARP syndrome). Neurology 45: 487-492, 1995.

*FIELD* CS
INHERITANCE:
Autosomal recessive

HEAD AND NECK:
[Eyes];
Retinitis pigmentosa

NEUROLOGIC:
[Central nervous system];
Dystonia;
Spasticity;
Orofacial dyskinesia;
Progressive dementia;
Dysarthria;
Dysphagia;
Pallidal degeneration;
Iron deposition in pallidal nuclei;
MRI shows decreased signal intensity in the pallidal nuclei with central
hyperintensity ('eye of the tiger' sign)

HEMATOLOGY:
Acanthocytes

LABORATORY ABNORMALITIES:
Hypoprebetalipoproteinemia

MISCELLANEOUS:
Two unrelated patients have been reported;
Onset in first or second decade;
Slowly progressive;
In 1 family, heterozygous mutations were associated with hypobetalipoproteinemia
and acanthocytes without neurologic abnormalities;
Allelic to the more severe pantothenate kinase-associated neurodegeneration
(NBIA1, 234200);
Distinguished from NBIA1 by the presence of hypobetalipoproteinemia
and acanthocytosis

MOLECULAR BASIS:
Caused by mutation in the pantothenate kinase-2 gene (PANK2, 607157.0011)

*FIELD* CD
Cassandra L. Kniffin: 1/14/2003

*FIELD* ED
ckniffin: 04/13/2010
terry: 2/19/2009
joanna: 1/16/2003
ckniffin: 1/16/2003

*FIELD* CN
Cassandra L. Kniffin - updated: 2/3/2004
Victor A. McKusick - updated: 9/17/2002

*FIELD* CD
Victor A. McKusick: 9/17/2002

*FIELD* ED
ckniffin: 04/13/2010
tkritzer: 2/6/2004
ckniffin: 2/3/2004
carol: 9/18/2002
tkritzer: 9/17/2002