{"doi":"10.1002/mds.29765","title":"A <scp><i>GNAI1</i></scp> Pathogenic Variant in a Case with <scp><i>GNAO1</i></scp>‐Isolated Dystonia: A Modifier of Disease Severity?","abstract":"Pathogenic variants in several genes encoding proteins associated with G-coupled protein receptors (GCPR), which are involved in the modulation of post-synaptic signalling and cyclic adenosine 3′,5′-monophosphate (cAMP) metabolism in striatal neurons, have been linked to hyperkinetic movement disorders, such as dystonia and chorea.1 GNAO1, encoding the G protein alpha subunit o (Gαo), is one of the major determinants of cAMP metabolism in the striatum.2 GNAO1 pathogenic variants cause a disabling childhood-onset movement disorder (MIM#617493), presenting with a variable combination of chorea, dystonia, and myoclonus, and are often associated with a severe developmental epileptic encephalopathy.3 Recently, milder cases presenting in late childhood or adolescence with an isolated movement disorder and less severe intellectual disability (ID) or epilepsy have been reported.4 However, determinants of phenotype severity in cases with GNAO1 pathogenic variants are unknown. We report a 17-year-old female patient with onset at age 10 of non-progressive isolated generalized dystonia with mild cervical, upper, and lower limb involvement (see Video 1 and supplementary information). Dystonia significantly improved with trihexyphenidyl (6 mg) daily. The patient also presented with mild ID and hypotonia during infancy. She had one single febrile seizure at age 4. The patient carried a previously reported de novo pathogenic variant in GNAO1 (NM_020988.2: c.535 A > G; p.Arg179Gly). Intriguingly, the patient carried an additional unreported likely pathogenic de novo variant in GNAI1 (NM_002069.5: c.40 G > C; p.Glu14Gln), encoding the GCPR-associated protein alpha-i1 subunit (Gαi1), which is also involved in cAMP metabolism.5 Pathogenic de novo missense variants in GNAI1 were recently identified in cases with severe ID, hypotonia, epilepsy, behavioral issues, and speech impairment, but no overt movement disorder (MIM#619854).5, 6 We speculate that the concomitant presence of these two GNAO1 and GNAI1 variants may be the reason for the milder clinical presentation in our patient. Gαo and Gαi1 exert opposite effects over adenylate cyclase 5 (AC5) activity in postsynaptic terminals, as Gαo indirectly increases AC5 activity while Gαi1 decreases it.2 Importantly, pathogenic GNAO1 variants are loss-of-function and lead to reduced AC5 activation and cAMP levels.2 On the contrary, it has been suggested that GNAI1 pathogenic variants may result in increased cAMP levels by disrupting the Gαi1 ability of inhibiting adenylate cyclase activity.5 As GNAO1 and GNAI1 pathogenic variants may exert opposite effects on cAMP levels, we hypothesize that the GNAI1 variant may counterbalance the reduction in cAMP levels caused by the GNAO1 variant and result in a milder clinical phenotype (Fig. 1). Vice versa, the presence of a GNAO1 variant may mitigate the cellular and clinical phenotype caused by the GNAI1 variant. This is consistent with the absence in our patient of severe developmental delay and seizures that are usually seen in other reported patients with GNAI1 variants.5 Notably, the same GNAO1 variant (p.Arg179Gly) was previously reported in a patient with upper body dystonia with onset in adolescence, moderate ID, and well-controlled episodes of partial seizures,7 a similar presentation to that of our case. Thus, it is also possible that the milder dystonic phenotype in our patient could be simply due to a less severe loss-of-function effect of this specific variant. Validation of these hypotheses will require further confirmation through functional studies. We thank the patient and her family for their participation in this study. (1) Research Project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing of the First Draft, B. Review and Critique. MHGM: 1A, 1B, 1C, 3A, 3B JSB: 1A, 1B, 1C, 3B LK: 1C, 3B DK: 3B NEM: 1A, 1B, 1C, 3A, 3B M.H.G.M. is an em","journal":"Movement Disorders","year":2024,"id":473095,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9613,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1308897,"name":"Joanna Blackburn","orcid":"0000-0002-4607-4641","position":1,"is_corresponding":false},{"id":742565,"name":"Lisa Kinsley","orcid":null,"position":2,"is_corresponding":false},{"id":273562,"name":"Dimitri Krainc","orcid":"0000-0002-4716-1886","position":3,"is_corresponding":false},{"id":384909,"name":"Niccolò E. Mencacci","orcid":"0000-0003-3383-9665","position":4,"is_corresponding":false},{"id":523731,"name":"Mariana H.G. Monje","orcid":"0000-0002-0730-4061","position":0,"is_corresponding":true}],"reference_count":7,"raw_metadata":null,"created_at":"2026-07-19T02:06:01.000126Z","pmid":"38419191","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}