Application of the Updated Movement Disorder Society Criteria for Prodromal Parkinson's Disease to a Population‐Based 10‐Year Study

(ACMG) criteria. Patient 2 is a 14-year-old male and the only child of healthy parents. At 3 years of age, he displayed isolated dysarthria because of oromandibular dystonia; an expressive language disorder was initially diagnosed. By 9 years of age writing dystonia and abnormal postures of neck and trunk become evident. At 13 years of age, on examination, he exhibited segmental dystonia with prominent cranial and cervical involvement and normal cognitive function. Treatment with anticholinergic (trihexyphenidyl 18 mg/day) resulted in mild improvement with no side effects. A concomitant brain MRI showed bilateral pallidal hypointensity on T2-weighted images, and a brain CT scan excluded intracranial calcifications (Fig. 1). Sanger sequencing of the THAP1 gene disclosed an in-frame deletion (c.207_209delCAA; p.Asn69del) inherited from the asymptomatic mother, confirming the clinical suspicious of DYT6. This variant, classified as supporting/ moderate pathogenesis (PM2-PP5) according to ACMG criteria, was previously found in 3 related and 2 unrelated patients with childhoodor adolescent-onset dystonia initially affecting the cervical muscles or the upper limbs; generalization of dystonia was reported in 4. One adult patient exhibited generalized chorea induced by trihexyphenidyl that persisted after drug withdrawal. In accordance with the neuroradiological finding, pathogenic variants in NBIA-associated genes (PLA2G6, PANK2, FTL, WDR45, COASY, C19orf12, FA2H) and KMT2B were excluded in both patients. Globus pallidus T2 hypointensities are the radiological hallmark of NBIA and reflects the accumulation of iron in the basal ganglia. Currently, 10 genes have been associated with NBIA (ATP13A2, C19orf12, COASY, CP, DCAF17, FA2H, FTL, PANK2, PLA2G6, and WDR45), but MRI findings resembling NBIA have been described in other conditions. Brain MRI is usually unrevealing in isolated monogenic dystonia, except for KMT2B-related dystonia (DYT28); specifically, approximately 25% of reported cases revealed abnormalities ranging from subtle and symmetric hypointense lateral streaks in the external globus pallidus to NBIA features. Our findings expand the radiological spectrum associated with DYT6 dystonia and advise including this condition with NBIA imitators.