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Metabolic and Volumetric Alterations in the Basal Ganglia and the Cerebellum in Dopa‐Responsive Dystonia in Symptomatic and Asymptomatic GCH1 Mutation Carriers

Year: 2026

Type: article

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: The aims were to characterize the volumetric and neurometabolic brain changes in GCH1 mutation carriers (MC) and explore their relationship with clinical severity. METHODS: P-MRSI) of the basal ganglia and cerebellum. Analysis of covariance (ANCOVA) was used for group comparisons, and correlations were assessed using clinical symptom severity rating scales. RESULTS: Volumetric analyses revealed enlarged globus pallidus (16.6%, P = 0.0010) and putamen (7.2%, P = 0.0310) volumes in sMCs and increased cerebellar gray matter in aMCs (8.0%, P = 0.0500). Nicotinamide adenine dinucleotide (NAD) levels were significantly reduced in the basal ganglia of carriers (NAD/Pi [inorganic phosphate]: -14.7%, P = 0.0460; NAD/ATP-α: -15.5%, P = 0.0180). In the cerebellum, aMCs demonstrated elevated high-energy phosphate ratios ([ATP-α + PCr]/Pi: 23.7%, P = 0.0170; ATP-α/Pi: 21.3%, P = 0.0460; PCr [phosphocreatine]/Pi: 25.2%, P = 0.0090) compared with sMCs and HCs. Smaller cerebellar volumes correlated with greater dystonia severity (Burke-Fahn-Marsden Dystonia Rating Scale, ρ = -0.557, P = 0.0133), whereas lower basal ganglia NAD ratios correlated with higher Movement Disorder Society-Unified Parkinson's Disease Rating Scale, Part III (ρ = -0.527, P = 0.0204), and Toronto Western Spasmodic Torticollis Rating Scale scores (ρ = -0.475, P = 0.0398). CONCLUSIONS: P-MRSI reveal region- and subgroup-specific metabolic and structural alterations in GCH1 MCs, linking basal ganglia vulnerability and cerebellar adaptation to clinical severity. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Source: Movement Disorders

DOI: 10.1002/mds.70332