This MRI and 31P‑MRSI study of GCH1 mutation carriers (20 symptomatic, 5 asymptomatic) reports enlarged globus pallidus/putamen in symptomatic carriers, reduced basal ganglia NAD ratios, and elevated cerebellar high‑energy phosphate ratios in asymptomatic carriers, with metabolic and volumetric…

The work links region‑specific NAD/energy metabolism deficits and cerebellar bioenergetic adaptation to motor severity, suggesting measurable metabolic biomarkers and potential NAD‑targeted therapeutic or biomarker avenues relevant to Parkinson's‑related basal ganglia vulnerability, though its…

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: We studied 20 sMCs, 5 aMCs, and 25 mutation-free healthy controls (HC) using volumetric magnetic resonance imaging (MRI) combined with 31phosphorus magnetic resonance spectroscopy imaging (31P-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: Volumetric MRI and 31P-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.