Amyotrophic Lateral Sclerosis

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2021-01-23

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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 neurodegenerative disease characterized by progressive muscular paralysis reflecting degeneration of motor neurons in the primary motor cortex, corticospinal tracts, brainstem and spinal cord.

Epidemiology

Incidence (average around 1/50,000 per year) and prevalence (average around 1/20,000) are relatively uniform in Western countries, although foci of higher frequency have been reported in the Western Pacific. The mean age of onset for sporadic ALS is about 60 years. Overall, there is a slight male preponderance (male to female ratio of around 1.5:1).

Clinical description

Approximately two thirds of patients with typical ALS have a spinal form of the disease (limb onset) and present with symptoms related to focal muscle weakness and wasting, in which onset of symptoms may start either distally or proximally in the upper and lower limbs. Gradually, spasticity may develop in the weakened atrophic limbs, affecting manual dexterity and gait. Patients with bulbar onset ALS usually present with dysarthria and dysphagia for solids or liquids. Limb symptoms can develop almost simultaneously with bulbar symptoms, and in the vast majority of cases will occur within 1-2 years. Paralysis is progressive and leads to death due to respiratory failure within 2-3 years for bulbar onset cases and 3-5 years for limb onset ALS cases.

Etiology

Most ALS cases are sporadic but 5-10% of cases are familial, and of these 20% involve a mutation of the SOD1 gene (21q22.11), about 2-5% involve mutations of the TARDBP gene (1p36.22) encoding the TAR DNA-binding protein 43 (TDP-43) and 1-2% involve mutations of the VCP gene (9p13.3) coding for the Valosin Containing Protein. Two percent of apparently sporadic cases involve SOD1 mutations, and TARDBP mutations have also been identified in sporadic cases.

Diagnostic methods

The diagnosis is based on clinical history, examination, electromyography, and exclusion of 'ALS-mimics' (e.g. multifocal motor neuropathy, Kennedy's disease (seethese terms) and cervical spondylotic myelopathy) by appropriate investigations. The pathological hallmarks comprise loss of motor neurons with intraneuronal ubiquitin-immunoreactive inclusions in upper motor neurons and TDP-43 immunoreactive inclusions in degenerating lower motor neurons. Signs of upper motor neuron and lower motor neuron damage not explained by any other disease process are suggestive of ALS.

Management and treatment

The management of ALS is supportive, palliative, and multidisciplinary. Non-invasive ventilation prolongs survival and improves quality of life. Riluzole is the only drug that has been shown to extend survival.