GNAL-associated dystonia: clinical spectrum, genetic features, and genotype-phenotype correlations

Despite increasing recognition of GNAL-associated dystonia as a genetic cause of adult-onset isolated cervical dystonia, the full phenotypic spectrum, longitudinal pattern of disease progression, and genotype-phenotype relationships remain incompletely defined. We retrospectively reviewed our case of genetically confirmed patient with GNAL-associated dystonia and reviewed genetically confirmed cases published up to June 2026. Demographic, clinical, treatment, neuroimaging, and genetic data were extracted. Genotype-phenotype comparisons were performed between patients with missense and loss-of-function (LoF) variants. Our review showed seventy-six patients, with a median age at onset of 35 years (IQR, 22-44) and female predominance (57.9%). Dystonia was predominantly focal at onset, with cervical dystonia being most common; and 54% patients with focal onset progressed to segmental or generalized dystonia, with a median time to generalization of 6 years. Most patients had isolated dystonia. Among 46 detected genetic variants, missense variants predominated and nearly all were heterozygous. Twelve patients underwent globus pallidus interna deep brain stimulation (GPi-DBS), with greatest benefit for cervical dystonia. The LoF variants were associated with a shorter time to generalization than missense variants (2 vs. 10 years, p=0.021). This association was not confirmed in a censoring-based survival analysis (log-rank p=0.904) and should be regarded as hypothesis-generating. GNAL-associated dystonia presents as adult-onset isolated dystonia with focal onset, with substantial longitudinal progression to segmental or generalized dystonia (54%). GPi-DBS appears beneficial, particularly for cervical dystonia. The genetic spectrum is highly heterogeneous, with predominantly heterozygous missense distributed across the α-helical and Ras-like GTPase domains. The observed association between LoF variants and more rapid generalization warrants validation in larger longitudinal cohorts.