Fabry GLA Gene Variant Found in Parkinson’s Patients
A variant in the GLA gene associated with Fabry disease was found in four women with Parkinson’s disease, but they had no Fabry symptoms, according to results from a study of 236 Parkinson’s patients.
According to the research team, the significance of the mutation and the relationship between the two diseases requires further investigation.
“The results of this study suggest a possible relationship between [Fabry] and [Parkinson’s] in a small proportion of cases,” the researchers wrote. “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 [Parkinson’s] needs further elucidation, and these findings should be interpreted with caution.”
The study, “Prevalence of Fabry Disease among Patients with Parkinson’s Disease,” was published in the journal Parkinson’s Disease.
Fabry is among a group of diseases called lysosomal storage disorders, which broadly involve the toxic accumulation of molecules in cells as a result of an enzyme deficiency preventing lysosomes — the cell compartments that break down excess or unwanted proteins — from doing their job.
In Fabry, mutations in the GLA gene cause a deficient or absent alpha-GalA enzyme that results in the buildup of two molecules, Gb3 and lyso-Gb3.
Lysosome dysfunction also is thought to be important in Parkinson’s disease, a neurodegenerative disease characterized by abnormal buildup of the alpha-synuclein protein. As such, there is an increasing interest in understanding the relationship between lysosomal storage diseases and Parkinson’s.
A previous study reported an increased prevalence of Parkinson’s among people with Fabry and their immediate relatives. Decreased alpha-GalA activity also has been reported in Parkinson’s patients, suggesting a relationship between the two diseases.
To systematically evaluate the relationship, the research team examined the prevalence of Fabry among 236 Parkinson’s patients recruited to a movement disorders center in Kosice, Slovakia.
Among the 130 male patients, 20 (15%) had low alpha-GalA levels. Lyso-GB3 levels were normal in these 20 men.
Of note, only one mutated copy of GLA is necessary to have Fabry. Since the gene is on the X chromosome, of which females have two copies, a second, healthy copy may allow females with one mutant copy to have normal enzyme levels. For this reason, measuring alpha-GalA levels is not considered as clinically useful for diagnosis in women, and thus was not performed in this study.
Genetic testing of the 20 alpha-GalA deficient males and all 106 female patients revealed that four, all of whom were female, had the same mutation in the GLA gene (c.937G>T).
Among these four women, the age of Parkinson’s onset was greater than 55 years. All four had typical motor symptoms of Parkinson’s, and non-motor symptoms of urinary problems, sleep issues, and mood problems were each reported in three of the four women. Two had normal cognition and two had mild cognitive impairment.
MRI scans showed typical signs of Parkinson’s, but no abnormalities consistent with Fabry. Further, no features suggestive of Fabry were observed in eye, kidney, and heart exams among the four women.
According to the researchers, while this mutation has been identified previously, it is still unclear whether it is disease-causing or a benign mutation that can occur in healthy people. Some studies have reported it as the cause of Fabry, and others found it to be insignificant.
While this study lacked healthy controls, a comparison of the prevalence of the variant in age-matched healthy people would help shed light on the matter, the researchers noted.
The interpretation is further complicated by the fact that female Fabry patients often are asymptomatic or show only mild symptoms. The women should be monitored for the emergence of symptoms, as should their sons, the team pointed out.
“Overall, the results of this study suggest that the [mutation] leads to a nonpathological or very mild variant of [Fabry] at most,” the researchers wrote.
“The clinical significance of the variant above mentioned is still under debate. Patients carrying the .. variant should be monitored annually, as enzyme replacement therapy could be used if organ manifestations occur,” they concluded.