In this study, we aim to define detailed clinical and genetic characteristics of patients with variants in OPTN from Turkey. Here we also describe the baseline characteristics, treatment and safety outcomes of three patients with OPTN-ALS treated with primidone, a RIPK1 inhibitor drug.

Previously linked to primary open-angle glaucoma, OPTN is now also identified as a rare cause of familial and sporadic ALS. Optineurin inhibits RIPK1-dependent inflammatory and cell death mechanism. Loss of optineurin function may sensitize motor neurons to RIPK1 kinase activation and RIPK1-dependent programmed cell death leading to ALS.

Ten patients diagnosed with definite or probable ALS according to El-Escorial criteria, who carried genetically confirmed pathogenic variants in OPTN. Primidone, FDA-approved drug for seizures has not been approved for ALS. We obtained signed informed consent from all patients, who then underwent 6-minute walk test (6MWT), ALSFRS-R and forced vital capacity. Serum NFL, RIPK and GFAP levels were also recorded.

Three patients were female and two were sporadic. The mean age of onset was 40 years. Upper motor neuron signs were prominent in all patients. Three homozygous pathogenic/likely pathogenic variant in the OPTN gene (NM_001008212.2) were identified (c.872del/p.(Gly291AlafsTer12), c.1078_1079delAA/(Lys360Valfs*18)  and (c.1400A>C/p.(Gln467Pro)). Three patient received primidone 250mg per day for three months. No changes in ALSFRS-R and FVC were observed at 3th month but the distance walked improved in two patients, mean baseline 6MWT distances was 87.5 m, mean 6MWT distance was 146.5 m after 3 months of treatment. Mean sNFL of these two was 38.1 pg/ml at baseline, 42.75 pg/ml at the first month and decreased to 35 pg/ml at 3th month. Mean sGFAP was also decreased from 128.5 pg/ml at baseline to 113.6 pg/ml at 3th month.

The clinical association of OPTN exhibits allelic heterogeneity. Repurposing primidone, an FDA approved RIPK inhibitor may have beneficial effects in OPTN-ALS.