Metabolic and volumetric alterations in the basal ganglia and the cerebellum in dopa-responsive dystonia in symptomatic and asymptomatic GCH1 mutation carriers

ABSTRACT Background Dopa-responsive dystonia is caused by pathogenic variants in the GCH1 gene. Although its clinical features and reduced penetrance are known, in vivo metabolic and structural alterations in symptomatic (sMC) and asymptomatic mutation carriers (aMC) remain poorly understood. Objectives To characterize volumetric and neurometabolic brain changes of GCH1 mutation carriers and explore their relationship with clinical severity. Methods We studied 20 sMC, 5 aMC, and 25 mutation-free healthy controls (HC) using volumetric MRI combined with 31 phosphorus magnetic resonance spectroscopy imaging ( 31 P-MRSI) of the basal ganglia and cerebellum. ANCOVA was used for group comparisons, and correlations were assessed with clinical symptom severity rating scales. Results Volumetric analyses revealed enlarged globus pallidus (+16.6%, p = 0.001) and putamen (+7.2%, p = 0.031) volumes in carriers and increased cerebellar gray matter in aMC (+8.0%, p = 0.050). NAD levels were significantly reduced in the basal ganglia of carriers (NAD/Pi: -14.7%, p = 0.046; NAD/ATP-α: -15.5%, p = 0.018). In the cerebellum, aMC demonstrated elevated high-energy phosphate ratios ((ATP-α+PCr)/Pi: +23.7%, p = 0.017; ATP-α/Pi: +21.3%, p = 0.046; PCr/Pi: +25.2%, p = 0.009) compared with sMC and HC. Smaller cerebellar volumes correlated with greater dystonia severity (BFMDRS, ρ = -0.475, p = 0.019) while lower basal ganglia NAD ratios correlated with higher MDS-UPDRS-III (ρ = -0.472, p=0.041) and TWSTRS scores (ρ = -0.477, p = 0.039). Conclusions 31 P-MRSI and volumetric MRI reveal region- and subgroup-specific metabolic and structural alterations in GCH1 mutation carriers, linking basal ganglia vulnerability and cerebellar adaptation to clinical severity.