Brain structural alterations in patients with <i>GCH1</i> mutations associated DOPA-responsive dystonia

GCH1 gene encodes the guanosine-5'-triphosphate (GTP) cyclohydrolase 1 (GTP-CH1), which is the enzyme involved in the first and rate-limiting step of the de novo biosynthesis of tetrahydrobiopterin and an essential cofactor for the synthesis of dopamine in nigrostriatal neurons. GCH1 mutation is the most common cause of the DOPA-responsive dystonia (DRD).1 This rare autosomal-dominant movement disorder is characterised predominantly by limb dystonia during childhood, although parkinsonian features may also be present.1 The hallmark of the disease is an excellent and sustained response to small doses of levodopa, generally without the occurrence of motor complications.1 Lack of changes in neuropathological and in majority of dopaminergic imaging studies in patients with GCH1 -related DRD suggest that this is a neurotransmitter rather than a neurodegenerative disorder.1 However, case reports showed a nigrostriatal dopaminergic denervation (abnormal DaTSCAN) in some individuals carrying GCH1 mutation with adult-onset dystonia-parkinsonism.2 Residual symptoms might partially result from a lack of timely therapy, possibly suggesting underlying neurodegeneration. It has been hypothesised that, after a period of compensation, chronic reduction of dopamine levels resulting from GTP-CH1 deficiency could predispose to nigral cell damage by making them more vulnerable to environmental or other genetic factors.2 To the best of our knowledge, no MRI studies have been performed to assess the presence of structural damage supporting the possible neurodegenerative process underlying DRD. In order to fill the gap in line with previous suggestions, in this study we used structural MRI (1.5 T) to evaluate patterns of cortical thickness, basal ganglia volumes, and white matter (WM) microstructural alterations …