The mutation D313Y may be associated with nervous system manifestations in Fabry disease

Zompola, Christina; Palaiodimou, Lina; Kokotis, Panagiotis; Papadopoulou, Marianna; Theodorou, Aikaterini; Sabanis, Nikolaos; Theodoroula, Efterpi; Papathanasiou, Matilda; Tsivgoulis, Georgios; Chroni, Elisabeth

doi:10.1016/j.jns.2020.116757

Cited by 12 publications

(13 citation statements)

References 6 publications

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“…These findings contradict other studies showing that the p. (Asp313Tyr) variant may lead to FD-nervous system manifestations [ 33 , 39 – 41 ]. Koulousios et al have shown the possibility that the p. (Asp313Tyr) variant might be considered as disease causing by finding that the prevalence of the p. (Asp313Tyr) variant among patients with FD is more than 35%, while the frequency in the general population is estimated to be less than 1% [ 41 ].…”

Section: Discussioncontrasting

confidence: 99%

“…Data in the Moulin study showed that the p. (Asp313Tyr) GLA variant may lead to symptoms and organ manifestations compatible with FD [ 40 ]. Also, Zompola et al reported two newly diagnosed Fabry cases with nervous system manifestations related to the p.(Asp313Tyr) variant, which strengthened the presumption of the pathogenicity of this mutation [ 33 ]. In a recent review of Effraimidis et al, the authors stated that the frequency of the p. (Asp313Tyr) variant in comparison to the general population is only higher in neurologic disorders [ 42 ].…”

Section: Discussionmentioning

confidence: 99%

“…According to the existing literature, more than 900 variants in the GLA gene have been described [ 31 ], but the specific clinical impact of most mutations has not yet been well explored [ 32 ]. Although substantial literature exists, it is still under debate whether the p. (Asp313Tyr) variant represents a disease-causing mutation, a low-pathogenic variant, or just a polymorphism [ 33 ]. In 1993, this mutation was reported as causative in a male patient with a classical manifestation of FD [ 34 ].…”

Section: Discussionmentioning

confidence: 99%

“…Preclinical detection of neurovascular involvement in FD might allow appropriate management and prevention of future cerebrovascular complications and disability [ 43 ]. Due to the findings stated previously, patients carrying the p.(Asp313Tyr) variant should be monitored annually, as enzyme replacement therapy could be used if organ manifestations occur [ 33 ].…”

Section: Discussionmentioning

confidence: 99%

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Prevalence of Fabry Disease among Patients with Parkinson’s Disease

Lackova

Beetz

Oppermann

et al. 2022

Parkinson's Disease

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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.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Prevalence of Fabry Disease among Patients with Parkinson’s Disease

Lackova

Beetz

Oppermann

et al. 2022

Parkinson's Disease

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“…This mutation was also encountered in the other four patients, who were asymptomatic with normal LysoGb3 values. This variant is considered of uncertain significance, following the American College of Medical Genetics and Genomics (ACMG) recommendations, and is widely reported in literature to have a low clinical significance [ 36 , 37 ], although there are some reports of patients carrying this variant, presenting with neurological symptoms [ 38 , 39 ].…”

Section: Discussionmentioning

confidence: 99%

Screening for Fabry Disease in Kidney Transplant Recipients: Experience of a Multidisciplinary Team

et al. 2020

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Fabry disease (FD) is a rare cause of end-stage renal disease requiring kidney transplantation. Data on the incidence of unrecognized FD in kidney transplant recipients are scarce and probably underestimated. This study evaluated the incidence of FD in a population of kidney recipients, with a particular focus of the multidisciplinary approach for an early clinical assessment and therapeutic approach. Two hundred sixty-five kidney transplant recipients were screened with a genetic analysis for α-galactosidase A (GLA) mutation, with measurement of α-Gal A enzyme activity and Lyso Gb3 levels. Screening was also extended to relatives of affected patients. Seven patients (2.6%) had a GLA mutation. Two patients had a classic form of FD with Fabry nephropathy. Among the relatives, 15 subjects had a GLA mutation, and two had a Fabry nephropathy. The clinical and diagnostic assessment was completed after a median of 3.2 months, and mean time from diagnosis to treatment was 4.6 months. This study reported a high incidence of unrecognized GLA mutations in kidney transplant recipients. Evaluation and management by a multidisciplinary team allowed for an early diagnosis and treatment, and this would result in a delay in the progression of the disease and, finally, in better long-term outcomes.

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