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.
Authors
Mahale Mahale, Khanda Khanda, Shravan Shravan, Roy Roy, Padmanabha Padmanabha, Mailankody Mailankody
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