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Background. An increased prevalence of Parkinson’s disease (PD) disease has been previously reported in subjects with Fabry disease (FD) carrying alpha-galactosidase (GLA) mutations and their first-line relatives. Moreover, decreased alpha-galactosidase A (AGLA) enzymatic activity has been reported among cases with PD compared to controls. Objective. The aim of our study was to determine the prevalence of FD among patients with PD. Methods. We recruited 236 consecutive patients with PD from February 2018 to December 2020. Clinical and sociodemographic data, including the MDS-UPDRS-III scores and HY stage (the Hoehn and Yahr scale), were collected, and in-depth phenotyping was performed in subjects with identified GLA variants. A multistep approach, including standard determination of AGLA activity and LysoGb3 in males, and next-generation based GLA sequencing in all females and males with abnormal AGLA levels was performed in a routine diagnostic setting. Results. The mean age of our patients was 68.9 ± 8.9 years, 130 were men (55.1%), and the mean disease duration was 7.77 ± 5.35 years. Among 130 men, AGLA levels were low in 20 patients (15%), and subsequent Lyso-Gb3 testing showed values within the reference range for all tested subjects. In 126 subsequently genetically tested patients, four heterozygous p.(Asp313Tyr) GLA variants (3.2%, MAF 0.016) were identified; all were females. None of the 4 GLA variant carriers identified had any clinical manifestation suggestive of FD. Conclusions. The results of this study suggest a possible relationship between FD and PD in a small proportion of cases. Nevertheless, the GLA variant found in our cohort is classified as a variant of unknown significance. Therefore, its pathogenic causative role in the context of PD needs further elucidation, and these findings should be interpreted with caution.

Despite the limitations, including a short follow-up period and small sample size, this pilot study suggests that FUS Vo-thalamotomy may be an alternative treatment option for patients with FHD. A randomized controlled study with a larger sample size and a longer follow-up period is warranted to elucidate the efficacy and safety of MRgFUS Vo-thalamotomy for FHD.Acknowledgments: We thank Kaoru Shimizu from the Intelligent Clinical Research and Innovation Center at the Tokyo Women's Medical University for her invaluable assistance in the conduct of this study.

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BackgroundProtein synthesis is a tightly controlled process, involving a host of translation‐initiation factors and microRNA‐associated repressors. Variants in the translational regulator EIF2AK2 were first linked to neurodevelopmental‐delay phenotypes, followed by their implication in dystonia. Recently, de novo variants in EIF4A2, encoding eukaryotic translation initiation factor 4A isoform 2 (eIF4A2), have been described in pediatric cases with developmental delay and intellectual disability.ObjectiveWe sought to characterize the role of EIF4A2 variants in dystonic conditions.MethodsWe undertook an unbiased search for likely deleterious variants in mutation‐constrained genes among 1100 families studied with dystonia. Independent cohorts were screened for EIF4A2 variants. Western blotting and immunocytochemical studies were performed in patient‐derived fibroblasts.ResultsWe report the discovery of a novel heterozygous EIF4A2 frameshift deletion (c.896_897del) in seven patients from two unrelated families. The disease was characterized by adolescence‐ to adulthood‐onset dystonia with tremor. In patient‐derived fibroblasts, eIF4A2 production amounted to only 50% of the normal quantity. Reduction of eIF4A2 was associated with abnormally increased levels of IMP1, a target of Ccr4‐Not, the complex that interacts with eIF4A2 to mediate microRNA‐dependent translational repression. By complementing the analyses with fibroblasts bearing EIF4A2 biallelic mutations, we established a correlation between IMP1 expression alterations and eIF4A2 functional dosage. Moreover, eIF4A2 and Ccr4‐Not displayed significantly diminished colocalization in dystonia patient cells. Review of international databases identified EIF4A2 deletion variants (c.470_472del, c.1144_1145del) in another two dystonia‐affected pedigrees.ConclusionsOur findings demonstrate that EIF4A2 haploinsufficiency underlies a previously unrecognized dominant dystonia‐tremor syndrome. The data imply that translational deregulation is more broadly linked to both early neurodevelopmental phenotypes and later‐onset dystonic conditions. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Skin manifestations are well-recognized non-motor symptoms of Parkinson's disease (PD) and other hypokinetic and hyperkinetic movement disorders. Skin conditions are usually well visible during routine clinical examination and their recognition may play a major role in diagnostic work-up. In this educational review we:(1) briefly outline skin conditions related to Parkinson's disease, including therapy-related skin complications and their management; (2) discuss the role of skin biopsies in early diagnosis of PD and differential diagnosis of parkinsonian syndromes; and focus more on areas which have not been reviewed in the literature before, including (3) skin conditions related to atypical parkinsonism, and (4) skin conditions related to hyperkinetic movement disorders. In case of rare hyperkinetic movement disorders, specific dermatological manifestations, like presence of angiokeratomas, telangiectasias, Mongolian spots, lipomas, ichthyosis, progeroid skin changes and others may point to a very specific group of disorders and help guide further investigations.