Prevalence of Fabry Disease among Patients with Parkinson's Disease.

Alexandra Lacková ,Mie Rizig,Sebastian Oppermann,Martin Cobej,Simona Liesenerova,Jana Cobejova,Petra Pavelekova,Henry Houlden,Petra Levicka,Daniela Sendekova,Christian Beetz,Viktoria Sukovska,Miriam Ostrožovičová ,Vladimír Haň ,Tatiana Lorincová ,Péter Bauer ,Kristína Kulcsarová ,Zuzana Gdovinová ,Matej Škorvánek

doi:10.1155/2022/1014950

Abstract

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.

Highlights

Fabry disease (FD) belongs to the group of genetically determined forms of lysosome storage disorders with X-linked inheritance, which lead to a deficiency of lysosomal enzyme–alpha-galactosidase A (AGLA), resulting in the accumulation of glycosphingolipids, especially globotriaosylceramide (Gb3) in vital organs [1]
Decreased AGLA enzymatic activity has been reported among cases with Parkinson’s disease (PD) compared to controls [2]. is points to a potential relationship between these two disorders. e function of the AGLA enzyme represents a new therapeutic approach for genetically determined PD, as increasing the levels of these enzymes leads to a reduction in the levels of alpha-synuclein [7]
Cognitive status was normal in 2 GLA p.Asp313Tyr positive subjects according to Montreal Cognitive Assessment (MoCA) and Parkinson’s Disease-Cognitive Rating Scale (PD-CRS), while 2 patients scored in the PD mild cognitive impairment range

Summary

Introduction

Fabry disease (FD) belongs to the group of genetically determined forms of lysosome storage disorders with X-linked inheritance, which lead to a deficiency of lysosomal enzyme–alpha-galactosidase A (AGLA), resulting in the accumulation of glycosphingolipids, especially globotriaosylceramide (Gb3) in vital organs [1]. An increased prevalence of PD disease has been previously reported in subjects with FD and their first-line relatives [6]. 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. Decreased alpha-galactosidase A (AGLA) enzymatic activity has been reported among cases with PD compared to controls. In 126 subsequently genetically tested patients, four heterozygous p.(Asp313Tyr) GLA variants (3.2%, MAF 0.016) were identified; all were females. The GLA variant found in our cohort is classified as a variant of unknown significance. erefore, its pathogenic causative role in the context of PD needs further elucidation, and these findings should be interpreted with caution

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Conclusion