Amyotrophic Lateral Sclerosis 22 With Or Without Frontotemporal Dementia

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Retrieved

2019-09-22

Source

Omim

Trials

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Genes

C9orf72, SOD1, PON1, ATXN2, FUS, TARDBP, TAF15, OPTN, SQSTM1, MATR3, TBK1, UNC13A, CHMP2B, NEK1, DAO, CFAP410, DCTN1, SIGMAR1, TREM2, CHCHD10, ANG, NEFH, UBQLN2, EPHA4, PFN1, HNRNPA1, VCP, VAPB, PRPH, SETX, HNRNPA2B1, PPARGC1A, DPP6, CCNF, ANXA11, GLT8D1, ERBB4, GLE1, FIG4, SCFD1, SLC1A2, EWSR1, PON2, PON3, GFAP, MOBP, TP53, ARHGEF28, PTGS2, SOD2, GSR, TNFRSF21, SLC6A1, CD40LG, PLA2G4A, CAMK1G, DBR1, GSTP1, ADARB1, CASP3, AQP4, C5AR1, C3, NEFM, KCNJ10, BCL2L1, ZNF106, KIF1B, MSTN, CASP9, PSMC4, PTPRZ1, RARA, EPG5, ALS2, CASP12, MAPT, IGF1R, IGF2R, TUBA4A, KIFAP3, KIF5A, TRPM7, SARM1, ATXN3, SPG11, PSEN1, TNIP1, SUSD2, MOB3B, DCDC2, HFE, CENPV, SUN3, CST3, DCTN4, ST3GAL3, GTF2H1, ICE1, GRN, CSF2, SUN2, GRIA2, CPNE4, LAMA3, LAMC2, PTBP1, STMN1, NUP62, STK36, MAK16, NUP98, NEFL, GABPA, SRRM2, RBMS3, NFE2L2, GRIP1, GDNF, ARAP2, APTX, SCN8A, NPEPPS, APP, KIAA0513, SMN1, ARHGEF2, WASHC5, SNURF, APOE, TIAM1, AR, NRXN1, TNF, IGFALS, KHDRBS1, IGF1, PNO1, VEGFA, BDNF, ACTB, BCL2, SNCA, SMN2, NME9, GTPBP1, CNTF, KIAA0040, PIGL, SNRPN, ADA, SIRT1, CCL2, GRM2, IL6, MAPK1, TIA1, CDK5, P2RX7, CHI3L1, GPNMB, RIPK1, MIR206, CHGB, CHIT1, P4HB, GRM5, PARP1, IL1B, HTT, TNFRSF1B, EPO, MIR338, LY6E, VGF, ABCB1, MCIDAS, GRM1, DECR1, APEX1, CYBB, PINK1, ZNF512B, XBP1, HCLS1, ADIPOQ, HGF, MMP9, LMNB1, ATG5, NGF, NRG1, SIGLEC7, GRIA1, TANK, DNM1L, KHSRP, FGF2, SS18L1, CSF3, TUSC2, IL2RB, PSIP1, HSPB1, RBM45, TCF3, RAN, CUX1, RNF19A, MAPK14, NLRP3, SMUG1, SFPQ, CASP1, AIF1, ZNF569, KEAP1, TPPP, MST1, CHCHD2, RNASE4, RBM8A, RREB1, MSC, TMEM189-UBE2V1, OXR1, TMEM189, CHGA, ATXN2-AS, RRM2, CX3CR1, ZNF629, ATF6, TMED9, CNR2, ASPM, ZNF253, NAIP, ELP3, LGALS3, HRES1, PPARG, UBE2V1, FMR1, ERN1, EPHB2, LCN2, HNRNPA1P10, HSF1, TTR, ASPA, ASIP, SEMA3A, VDAC1, ZNF763, A1CF, TLR4, CAT, CCS, THY1, ZNF436, HSPA4, ROPN1L, NIPA1, EDN1, CDK5R1, TGM2, TNPO1, CASZ1, CXCL8, RTN4, LGALS1, RNASEL, TMEM106B, S100A6, SLC1A1, SOX2, STAT3, TFAM, TGFB1, SUMO1, AHSA1, SLC35A1, VRK1, CLEC10A, AIMP2, ELP1, HNRNPDL, VAPA, GRAP2, S100B, RRM1, VPS54, RNASE1, MSMB, FIS1, COX2, FOXP3, NOS1, NOS2, NTF3, P2RX4, HSPB8, PIN1, POLDIP2, PTPA, MAP2K5, PRNP, RAG2, IL4, GAL3ST1, CRK, AGER, HNRNPH2, ADAR, HNRNPC, CRP, EGFR, ADCYAP1, LMLN, MIR155, PRMT1, SUGP1, ANPEP, HNRNPH1, MTOR, CST12P, FXN, C19orf12, PDIA3, CTNNB1, GAPDH, TMPRSS13, CYP27A1, HIF1A, CS, LRRK2, IFNG, ALAD, DES, CP, CCL27, FCGR3A, PPIA, PHGDH, SLC52A3, FCGR3B, CFDP1, NEAT1, SPAG11B, ATRNL1, SLC30A3, ATM, PRRT2, SYT1, FMO1, CST7, GAP43, PDLIM3, GSTK1, SIRT2, XIAP, DENR, CAV1, SLPI, CAST, TFEB, FN1, CCR2, PRKN, APRT, STMN2, TLR2, TFPI2, ATHS, PDC, MAPK8, CREBBP, UCHL1, MOK, NOP56, SLCO6A1, RANBP2, ATG7, DNMT1, RASGRF1, UCP2, RELA, TSPO, PRKCA, TXN, CTBS, SIRT3, RRAD, TTN, CTF1, ATP13A2, TRPM2, ATXN1, RAB5A, DAPK2, PVALB, UTRN, PRKCB, XBP1P1, FBXO32, SPAG11A, BECN1, RAB3GAP2, WNT5A, EPHA3, EPHA1, VSNL1, CRMP1, VIM, EIF4G2, PSMD2, SGCG, VDR, PTGER2, TNFRSF1A, EGF, HPGDS, GARS1, TSHZ1, MAOB, SNPH, HDAC4, SRR, NAT10, SPAST, LIG4, LRP4, MIR146A, HMOX1, HMGB1, LSM2, MAP2, SIL1, GORASP1, PDIA2, MTHFSD, NPY, ERVK-12, SOX9, ERVK-2, LEP, ERVK-11, MFAP1, MTCO2P12, GJD2, IL10, RIPK3, DDX20, ABL1, SLC17A6, STAT5A, PCYT1B, IGF2, CTR9, FGGY, TDP1, CCDC88A, HDAC9, ABCG2, MFN1, KDR, TEAD1, RHOT1, DNAJB2, MET, ERVK-22, KITLG, CHAF1A, LINC01672, CHI3L2, UBQLN1, MALAT1, FNDC3A, GLS, PADI1, ASRGL1, NRP1, CLU, GH1, SNAP25, RAB11A, DBNL, NFKB1, ALYREF, MIR1825, CCN2, NOTCH1, KCNIP3, HSP90B2P, PIK3R4, ARHGEF7, ALB, GEMIN4, ALPP, SOS1, HDAC6, ALS3, DERL1, WNK1, AKT1, GPX3, HDAC1, MTHFR, SLC25A37, AKT3, PNPLA6, LILRA2, MIR193A, RBBP9, PAPOLA, NES, YWHAQ, ARPP21, MIR29B1, MIR93, JTB, MIR29B2, MRPS30, MIR143, MIR23A, MIR15A, MIR183, ERGIC1, OGA, P2RX5-TAX1BP3, OLIG2, EBI3, NAMPT, MIR4299, PPIF, ABCC9, SH2B3, OCLN, FGFBP1, MFN2, MIR4649, CALCOCO2, PINK1-AS, LZTS3, ELDR, TPTEP2-CSNK1E, GDA, CREB5, H3P13, CCL4L2, PTGES, BAG3, GDF11, GLYAT, TSBP1, LOC643387, MIR17HG, MIR326, MIR375, ERLIN1, MIR378A, MIR494, MIR193B, MIR524, ZNF704, POU5F1P3, POU5F1P4, RAMP3, CARM1, UNC13B, MIR582, OLFM1, RACK1, TUBA1B, MIR638, LANCL1, STUB1, MIR1246, POTEF, CLEC4C, MIR142, NOP53, SRCIN1, RUBCNL, IFT74, UBN1, ATAT1, DHDDS, SLC40A1, FLVCR1, KCNIP1, ASAP1, GGNBP2, ASCC1, HDAC11, ATL1, ARHGAP24, REM1, MIR139, TTBK1, PABPC1, CYFIP2, NOX1, ATAD1, ANKRD1, CACYBP, AGO2, HTRA2, HCAR1, TUBGCP4, BTBD10, COQ2, POLDIP3, EIF3K, GEMIN6, MMP28, NMD3, NLN, FAM160B1, SLC30A6, MAGEE1, NGLY1, KCNT1, ZKSCAN7, PRMT8, APH1A, LXN, FAM20C, NUP107, SLC12A5, NDRG2, MCOLN1, SAGE1, HAMP, NGB, WDR41, RMDN3, MTPAP, COP1, WIPI1, XRN1, P2RY12, DCUN1D1, IL23A, SIRT6, BCL11B, IGF2-AS, ACD, CUEDC2, BSCL2, AATF, WNT3A, CAMTA1, HCA1, NUP205, ATG4B, MLC1, PLCB1, ALS2CL, MGRN1, TICAM1, BICD2, SPDYA, HNRNPA3, MED19, FLCN, SIRT5, WDTC1, MIF-AS1, TAAR6, MYH15, P2RX2, GADL1, TGM6, ERCC6L2, KMT5A, ATG14, CCL4L1, AAK1, MGLL, MIRLET7B, PDAP1, MIR126, PARK7, JPH3, TTBK2, FGF21, GLCE, GRIN3B, NT5C3B, CARD16, AZIN2, L3MBTL1, OSBPL3, EGLN3, SYT9, DNER, NOC2L, MTDH, MCU, SPAG8, ANKRD2, THEM4, PANX1, ZFYVE27, TFIP11, PPIL2, SLC7A11, PPP1R15A, TPH2, CD2AP, JDP2, PDSS1, DDX58, PPARGC1B, PADI4, TRIM69, CABIN1, SMCR8, A1BG, SUMO2, GDF15, GHR, GJB1, GCLM, GLUL, CXCR3, GPX7, GRIA3, GRIA4, GRIK1, GRIN2A, GRM3, CXCL1, GSK3B, HADHA, HDAC2, HEXA, HK1, HLA-B, MNX1, HLA-DRB1, HLA-DRB5, HLA-F, GJA1, GFRA1, ADAMTS3, GEM, ESR1, ESR2, ETS2, EZH2, F9, PTK2B, FGF1, FGF13, FKBP4, FKBP5, FMO3, AFF2, FPR2, FRAXE, FTH1, FTL, FZD2, GBA, GBAP1, GC, GCG, HMOX2, HNMT, HNRNPK, HP, ITGB2, ITPR1, ITPR2, ITPR3, JAG2, JAK3, KCNJ8, KCNJ11, KCNK2, KIF5B, KIR3DL1, LAMC1, LGALS2, LGALS4, LIF, FADS3, LTBR, LUM, SH2D1A, MARCKS, MAP1B, ISG20, IRF3, IRF1, IFRD1, HPGD, AGFG1, HES1, HSPA8, HSPB2, DNAJB1, HTC2, ID2, IFNGR1, IGFBP5, INPP5B, IGFBP7, IL1A, IL2, IL2RA, IL13, IL15, IL17A, IL18, CXCL10, EREG, EPHB1, ENG, CD36, BAG1, BAX, BBS2, CCND1, BMP4, BNIP1, BNIP3L, BRCA1, CACNA1A, CACNA1S, CALB1, CALB2, CALR, CAMK4, CAPG, CAPN1, CAPN2, CASR, CBR1, CBS, CD14, ATP7A, ATP5F1A, ARG1, ADH5, AOC1, ACAT2, ACHE, ACP3, ACTA1, ACTN3, ACY1, ADARB2, ADCYAP1R1, JAG1, FAS, AHR, AK4, ALOX5, ALOX15, AMPH, ANGPT1, APCS, APOA1, APOB, CD34, CD40, ELAVL4, CD59, CTSL, CYP1A1, CYP1A2, CYP2D6, CYP19A1, ACE, DCX, DDIT3, DDX3X, DHFR, DLD, DMD, DYNC1H1, DNMT3A, DPYD, DPYSL2, EFNA5, EFNB1, CELSR3, EGR1, ELAVL1, CTSD, CSNK1E, CSNK1D, TBCB, CD68, CDK2, CDK9, CDKN2A, CDKN2D, CEBPD, CTSC, CEACAM4, CHRNG, ABCC2, CRYM, CNR1, CNTFR, COL4A2, COL11A2, COL19A1, CORD1, MAP3K8, COX8A, CREB1, MB, MBP, MC4R, RNF112, TAT, TGFB2, TIMP1, TIMP2, TIMP3, CLDN5, TP73, TPO, NR2C2, TRN-GTT2-1, DNAJC7, UBC, UBE2H, UCP1, UCP3, SCGB1A1, UGCG, XDH, XPO1, XRCC1, XRCC5, MAP3K7, TACR1, TAC1, SOAT1, SHBG, SHH, SI, SLC1A3, SLC8A3, SLC12A2, SLC12A4, SUMO3, SERPINA3, SOD3, SYP, SOX5, SOX10, SPP1, SREBF1, SST, SULT1E1, STXBP1, SUPT4H1, ABCC8, YWHAZ, TUBA1A, SEL1L, CXCR4, MGAM, HSPB3, SELENBP1, UNC119, INA, P2RX6, SLC33A1, XPR1, KLF4, ZNHIT3, CD163, LONP1, KL, CHST2, GSTO1, MAP4K4, EIF2AK3, HOMER1, PICK1, ROCK2, ADAMTS4, RAB29, BCL10, CACNA1H, DYNLL1, SCG2, PABPN1, CDC7, GEMIN2, MAP4K3, PPM1D, FCN3, BLZF1, LGR5, TNKS, SYNJ2, DGAT1, TNFSF14, TNFRSF10B, IL18R1, PROM1, ASAP2, ALDH1A2, NR1I2, SYNJ1, SGK1, CX3CL1, DNAJB9, P2RY2, MYOD1, NAP1L1, CEACAM6, NCAM1, NEDD8, NEUROG1, NFIL3, NGFR, NONO, SLC11A2, NRF1, NRGN, NTF4, NTRK1, NTRK2, NTRK3, OPA1, OSBP, P2RX1, P2RX3, P2RX5, MYO6, MYH9, MYH6, MMP14, MDH1, MECP2, MEF2A, MEF2C, MAP3K5, MICE, MIF, MIP, MMP7, MPZ, MYC, MRC1, MS, MT1A, MT1B, ATP6, NUDT1, ND5, MUSK, MYBPH, P2RY1, PAH, CCL18, REG3A, PTPRN, PURA, RAB1A, RANGAP1, RBP4, REG1A, UPF1, REST, RET, TRIM27, ROS1, RPS17, RPS25, RPS27A, SORT1, S100A4, S100A8, S100A9, SCD, SCNN1A, CCL4, PTGER3, PTEN, PTAFR, PLEC, PAWR, PCBP1, PCSK2, SERPINF1, PFN2, PGK1, PHB, SERPINA1, PLCD1, PLP1, PSMA7, PLXNA2, POMC, POU5F1, PPID, PKN1, MAPK3, MAPK9, EIF2AK2, PSAP, H3P40

Drugs

(R)-troloxamide quinone, None, Allogeneic motor neuron progenitor cells derived from human embryonic stem cells ( MOTORGRAFT )

(R)-troloxamide quinone, None, Allogeneic motor neuron progenitor cells derived from human embryonic stem cells ( MOTORGRAFT ), Ambroxol hydrochloride, Arimoclomol, Autologous adipose derived mesenchymal stromal cells, Autologous bone marrow-derived mesenchymal stromal cells secreting neurotrophic factors, Autologous olfactory neural progenitors, Caprine hyperimmune serum against HIV lysate, DNA plasmid vector (pCK-HGFX7) expressing human hepatocyte growth factor, Dexpramipexole, Edaravone ( RADICAVA ), Enoxacin, Filgrastim ( GRASTOFIL, BIOGRASTIM, FILGRASTIM HEXAL, ACCOFIL, NEUPOGEN, NIVESTIM, TEVAGRASTIM, RATIOGRASTIM, ZARZIO ), H-Leu-Pro-Pro-Leu-Pro-Tyr-Pro-OH, Human culture expanded autologous mesenchymal stromal cells, Hydrocinnamate-[Orn-Pro-dCha-Trp-Arg]acetate, Ibudilast, Levosimendan, Masitinib mesilate, Olesoxime, Oligopeptide containing 6 amino acids (H-Phe-Ser-Arg-Tyr-Ala-Arg-OH), Recombinant human antibody directed against misfolded human superoxide dismutase 1, Recombinant human cerebral dopamine neurotrophic factor (CDNF), Recombinant human vascular endothelial growth factor, Recombinant humanised monoclonal antibody to human Nogo-A protein of the IgG1/kappa class, Reldesemtiv, Riluzole ( RILUTEK ), S[+] apomorphine, Sarsasapogenin, Smilagenin, Sodium chlorite, Sodium phenylbutyrate, tauroursodeoxycholic acid, Synthetic ribonucleic acid oligonucleotide directed against superoxide dismutase 1 (SOD-1) messenger ribonucleic acid, Talampanel, Tauroursodeoxycholic acid (TUDCA), Tirasemtiv, Xaliproden hydrochloride, adeno-associated viral vector serotype 9 encoding miRNA against human superoxide dismutase 1

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A number sign (#) is used with this entry because of evidence that amyotrophic lateral sclerosis-22 with or without frontotemporal dementia (ALS22) is caused by heterozygous mutation in the TUBA4A gene (191110) on chromosome 2q35.

For a phenotypic description and a discussion of genetic heterogeneity of amyotrophic lateral sclerosis (ALS), see ALS1 (105400).

Clinical Features

In their study of familial ALS caused by mutations in the TUBA4A gene, Smith et al. (2014) found that all patients carrying TUBA4A mutations had spinal-onset classical ALS with upper and lower motor neuron signs. Two cases also developed a cognitive decline of frontal type, consistent with a diagnosis of frontotemporal dementia (FTD; 600274), and another had a first-degree relative with FTD.

Molecular Genetics

Smith et al. (2014) performed an exomewide rare variant burden analysis in 363 index cases with familial ALS (FALS) from 6 countries. In this discovery cohort, Smith et al. (2014) identified 5 nonsynonymous TUBA4A changes, all localized in exon 4 and confirmed by Sanger sequencing. None of the mutations was observed in 4,300 controls from the Exome Variant Server database, and all occurred at highly conserved positions. The mutations included 2 missense mutations in the same residue (R320C, 191110.0001 and R320H, 191110.0002) a nonsense mutation (W407X; 191110.0003) removing the last 41 amino acids, and 2 additional missense mutations (R215C, 191110.0004 and A383T, 191110.0005). Because no relatives of the affected patients were available to test segregation, Smith et al. (2014) sequenced an independent replication cohort comprising 272 index FALS cases and 5,510 internal European American controls for rare damaging exon 4 variants. In the replication cohort, 2 cases (0.65%) were identified versus 2 controls (0.04%, p = 1.5 x 10(-2)). A combined analysis of the discovery and replication cohorts resulted in a statistically significant overabundance of rare variants after multiple test correction (odds ratio = 36, 95% confidence interval: 10-210, corrected p = 4.2 x 10(-3)).