Objective: To investigate whether carriers of pathogenic GCH1 variant reveal lower NAD levels in the basal ganglia or the cerebellum compared to variant-free controls.

Background: GCH1 variants are associated with neurological disorders, including dopa-responsive dystonia, yet their impact on nicotinamide adenine nucleotide, NAD, and cerebral energy metabolism remains unclear. NAD plays a vital role in cellular energy production and neuronal function, with potential implications for disease pathogenesis.

Method: Twenty-five carriers of pathogenic GCH1 variant (19 symptomatic, i.e., dopa-response dystonia, and six asymptomatic) and twenty-five age-and sex-matched mutation-free healthy controls (HCs) underwent clinical evaluations, and multimodal neuroimaging, including ³¹phosphorus magnetic resonance spectroscopy imaging (³¹P-MRSI) targeting the basal ganglia and the cerebellum. Ratios of total NAD to ATP (NAD/ATP) derived from ³¹P-MRSI were used for group comparisons (using age, sex, and the total intracranial volume, TIV, as covariates). We also performed exploratory analyses to see if the penetrance status of carriers of pathogenic GCH1 variant might impact NAD/ATP levels.

Results: Carriers of pathogenic GCH1 variant showed lower NAD/ATP levels in the basal ganglia but not in the cerebellum (-13.7%, ANCOVA: F(45,1)=5.99, p=.018) compared to variant-free controls. These findings were not impacted by sex or TIV but moderately by age (p=.048). NAD/ATP levels were not different between symptomatic and asymptomatic carriers of pathogenic GCH1 variant.

Conclusion: Our study reveals lower NAD/ATP levels in the basal ganglia of carriers of pathogenic GCH1 variant, regardless of symptomatic status. These findings could be caused by increased NAD-dependent recycling of tetrahydrobiopterin (via dihydropteridine reductase) due to GCH1 deficiency, and highlight the potential for targeting NAD metabolism in this disorder.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/alterations-of-nad-metabolism-in-symptomatic-and-asymptomatic-carriers-of-pathogenic-gch1-variant/