Prevalence of Fabry Disease among Patients with Parkinson’s Disease

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.

Reader Response: D313Y Variant in Fabry Disease: A Systematic Review and Meta-analysis

“…The D313Y variant was identified in 4/127 subjects with allele frequency of 1.6% compared with 0.3% reported in the general population. 3 Similarly, in our cohort of consecutively screened subjects with multiple sclerosis using the same methodology, 2 the GLA D313Y variant was identified in 6/180 subjects (all female subjects), with an allele frequency of 1.7%, similar to that of PD subjects (previously unreported).…”

“…We agree with their findings and would like to expand the spectrum of neurologic diagnoses associated with increased prevalence of the D313Y variant. As reported in our recent study, 2 127 consecutive subjects with Parkinson disease (PD) were screened for the presence of GLA variants. The D313Y variant was identified in 4/127 subjects with allele frequency of 1.6% compared with 0.3% reported in the general population.…”

Author Response: D313Y Variant in Fabry Disease: A Systematic Review and Meta-analysis

“…We thank Lackova et al for their comments on our systematic review and meta-analysis regarding D313Y -variation in Fabry disease (FD) and for presenting their interesting findings. 1,2 Although parkinsonism is not considered a typical FD manifestation, 3 the reported prevalence of D313Y variant in this single-center cohort of patients with Parkinson disease was higher compared with the general population. 2 Furthermore, misdiagnosis of multiple sclerosis (MS) in patients with an ultimate FD diagnosis has been previously reported, mandating the consideration of FD during differential diagnosis for MS, especially when atypical multisystemic findings or positive family history exists.…”

Neurological Manifestations of Fabry Disease: Literature Review

“…In a study conducted in 2018 to 2020 in which 126 of 236 patients diagnosed with PD (20 men and 106 women with low FD biochemical markers) had their GLA gene sequenced. As a result, 4 patients (3.2%) with a significant genetic mutation were identified, all four were women, without other clinical manifestations of FD [33]. The authors state that the results of these studies suggest that individuals with GLA mutations may have an increased risk of developing PD, but these results should be interpreted with caution, given the limitations of the study design [31], [32], [33].…”