Amyotrophic Lateral Sclerosis 19

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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 amyotrophic lateral sclerosis-19 (ALS19) is caused by heterozygous mutation in the ERBB4 gene (600543) on chromosome 2q34.

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

Clinical Features

Takahashi et al. (2013) reported 3 Japanese sibs with onset of classic ALS between 60 and 70 years of age. They had relatively slowly progressive upper and lower motor neuron involvement without cognitive impairment. Two patients became ventilator-dependent and all 3 developed the locked-in state. Their deceased father was reportedly affected, but was not examined. An unrelated individual of Canadian origin had a similar disorder, with a positive family history. An additional Japanese proband with sporadic ALS showed earlier onset at 45 years of age and became wheelchair-bound.

Inheritance

The transmission pattern of ALS in the families reported by Takahashi et al. (2013) was consistent with autosomal dominant inheritance, and the authors postulated incomplete penetrance.

Molecular Genetics

In 3 Japanese sibs with late-onset amyotrophic lateral sclerosis-19, Takahashi et al. (2013) identified a heterozygous missense mutation in the ERBB4 gene (R927Q; 600543.0001). The mutation was found by whole-genome sequencing after exclusion of mutations in several known ALS-associated genes, and was consistent with linkage analysis. Sequencing of the ERBB4 gene in 364 familial ALS and 818 sporadic ALS cases identified 1 Canadian individual with familial ALS who also carried the same heterozygous R927Q mutation and a Japanese individual with sporadic ALS who carried a different de novo heterozygous missense mutation (R1275W; 600543.0002). The patients with the R927Q mutation had onset of classic upper and lower motor neuron degeneration between 60 and 70 years of age, whereas the patient with the R1275W mutation had earlier onset at age 45. In vitro functional expression studies in COS-7 cells showed that the mutant ERBB4 proteins had decreased autosphosphorylation upon NRG1 (142445) stimulation compared to wildtype. The findings suggested that disruption of the neuregulin-ERBB4 pathway is involved in the pathogenesis of ALS.