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. 2023 Aug;38(6):1905-1912.
doi: 10.1007/s11011-023-01216-4. Epub 2023 Apr 25.

Late-onset fabry disease due to the p.Phe113Leu variant: the first italian cluster of five families

Vittoria Cianci #  1 , Angelo Pascarella #  1   2 , Lucia Manzo #  1   2 , Sara Gasparini  1   2 , Oreste Marsico  1   2 , Anna Mammì  2 , Carmelo Massimiliano Rao  3 , Claudio Franzutti  4 , Umberto Aguglia  5   6 , Edoardo Ferlazzo  1   2
Affiliations

Late-onset fabry disease due to the p.Phe113Leu variant: the first italian cluster of five families

Vittoria Cianci et al. Metab Brain Dis. 2023 Aug.

Abstract

Background: The GLA c.337T > C (p.Phe113Leu) is a known pathogenic variant associated to late-onset Fabry disease phenotype with predominant cardiac manifestations. A founder effect was demonstrated in a large cohort in the Portuguese region of Guimarães. Herein we report an in-depth phenotype description of a cluster of five Southern Italy families.

Methods: Family pedigrees of five index males with the p.Phe113Leu variant were obtained and all at-risk relatives underwent biochemical and genetical screening test. Carriers of GLA p.Phe113Leu variant underwent subsequent multidisciplinary clinical and instrumental evaluation.

Results: Thirty-one (16 M, 15 F) individuals with p.Phe113Leu pathogenic variant were identified. Sixteen out of 31 patients (51.6%) had cardiac manifestations. Notably, myocardial fibrosis was found in 7/8 patients, of whom 2 were under 40 years. Stroke occurred in 4 patients. White matter lesions were detected in 12/19 patients and occurred in 2/10 of subjects under 40 years. Seven females complained of acroparesthesias. Renal involvement occurred in 10 patients. Angiokeratomas were evident in 9 subjects. Eyes, ear, gastrointestinal and pulmonary involvement occurred in the minority of subjects.

Conclusion: This study demonstrates that a cluster of subjects with p.Phe113Leu pathogenic variant is also present in Southern Italy. Disease manifestations are frequent in both sexes and may occur early in life. Cardiac involvement represents the core manifestation, but neurological and renal involvement is also frequent, suggesting that extra-cardiac complications deserve clinical attention.

Keywords: Cardiac phenotype; Late-onset Fabry Disease; Neurological phenotype; Stroke; p.Phe113Leu (p.F113L) pathogenic variant.

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Figures

Fig. 1
Fig. 1
Family pedigrees from the five patients with GLA p.Phe113Leu variant Index patients are marked with a black arrow. Numbers within symbols denote number of male or female relatives; question mark denotes subjects unavailable for biochemical and genetic evaluation due to refusal or death
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