Amyotrophic lateral sclerosis (ALS), the most common motor neuron disease in adults, is characterized by progressive loss of upper and lower motor neurons. Mutations in the superoxide dis-mutase gene (SOD1) account for about 20% of familial ALS cases. Here, we report Gly148Asp mutations in the exons of the SOD1 gene in two patients with familial ALS characterized by rapid progression of the disease, primarily affecting inferior motor neurons. Both patients developed severe systemic muscle atrophy and respiratory failure within one year of onset, having a short survival time. 

1.Brooks BR, Miller RG, Swash M, et al. El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis[J]. Amyotroph Lateral Scler Other Motor Neuron Disord, 2000, 1(5): 293-299. DOI: 10.1080/146608200300079536.

2.Li W, Gao H, Dong X, et al. SQSTM1 variant in disorders of the frontotemporal dementia-amyotrophic lateral sclerosis spectrum: identification of a novel heterozygous variant and a review of the literature[J]. J Neurol, 2021, 268(4): 1351-1357. DOI: 10.1007/s00415-020-10283-x.

3.Zarei S, Carr K, Reiley L, et al. A comprehensive review of amyotrophic lateral sclerosis[J]. Surg Neurol Int, 2015, 6: 171. DOI: 10.4103/2152-7806.169561.

4.Oskarsson B, Gendron TF, Staff NP. Amyotrophic lateral sclerosis: an update for 2018[J]. Mayo Clin Proc, 2018, 93(11): 1617-1628. DOI: 10.1016/j.mayocp.2018.04.007.

5.Chesi A, Staahl BT, Jovičić A, et al. Exome sequencing to identify de novo mutations in sporadic ALS trios[J]. Nat Neurosci, 2013, 16(7): 851-855. DOI: 10.1038/nn.3412.

6.Renton AE, Chiò A, Traynor BJ. State of play in amyotrophic lateral sclerosis genetics[J]. Nat Neurosci, 2014, 17(1): 17-23. DOI: 10.1038/nn.3584.

7.Rosen DR. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis[J].Nature, 1993, 364(6435): 362. DOI: 10.1038/364362c0.

8.Anzai I, Tokuda E, Handa S, et al. Oxidative misfolding of Cu/Zn-superoxide dismutase triggered by non-canonical intramolecular disulfide formation[J]. Free Radic Biol Med, 2020, 147: 187-199. DOI: 10.1016/j.freeradbiomed. 2019.12.017.

9.Zou ZY, Zhou ZR, Che CH, et al. Genetic epidemiology of amyotrophic lateral sclerosis: a systematic review and meta-analysis[J]. J Neurol Neurosurg Psychiatry, 2017, 88(7): 540-549. DOI: 10.1136/jnnp-2016-315018.

10.Pansarasa O, Bordoni M, Diamanti L, et al. SOD1 in amyotrophic lateral sclerosis: "ambiva-lent" behavior connected to the disease[J]. Int J Mol Sci, 2018, 19(5): 1345. DOI: 10.3390/ijms19051345.

11.Mathis S, Couratier P, Julian A, et al. Management and therapeutic perspectives in amyo-trophic lateral sclerosis[J].Expert Rev Neurother, 2017, 17(3): 263-276. DOI: 10.108 0/14737175.2016.1227705.

12.Yedavalli VS, Patil A, Shah P. Amyotrophic lateral sclerosis and its mimics/variants: a com-prehensive review[J]. J Clin Imaging Sci, 2018, 8: 53. DOI: 10.4103/jcis.JCIS_40_18.

13.Deverman BE, Ravina BM, Bankiewicz KS, et al. Gene therapy for neurological disorders: progress and prospects[J]. Nat Rev Drug Discov, 2018, 17(9): 641-659.DOI: 10.1038/nrd.2018.110.

14.Keeler AM, Zieger M, Semple C, et al. Intralingual and intrapleural AAV gene therapy prolongs survival in a SOD1 ALS mouse model[J]. Mol Ther Methods Clin Dev, 2019, 17: 246-257. DOI: 10.1016/j.omtm.2019.12.007.

15.Bravo-Hernandez M, Tadokoro T, Navarro MR, et al. Spinal subpial delivery of AAV9 enables widespread gene silencing and blocks motoneuron degeneration in ALS[J].Nat Med, 2020, 26(1): 118-130. DOI: 10.1038/s41591-019-0674-1.

16.Bonafede R, Mariotti R. ALS pathogenesis and therapeutic approaches: the role of mes-enchymal stem cells and extracellular vesicles[J]. Front Cell Neurosci, 2017, 11: 80. DOI: 10.3389/fncel.2017.00080.