#2456 Real world outcomes of Fabry disease in Italian excellence centers: the ground study
Authors: Pisani Antonio , Olivotto Iacopo , Mignani Renzo , Pieruzzi Federico , Tuttolomondo Bruno , Noto Davide , Pieroni Maurizio , Verrecchia Elena , Ingrassia Eleonora , Armaroli Annarita 
Published: May 2024

Abstract

Background and Aims
Fabry disease (FD) is an X-linked lysosomal storage disorder with an estimated prevalence from 1:1368 to 1:8882, caused by galactosidase alpha gene (GLA) mutations, resulting in renal, cardiac and central nervous system involvement with significant morbidity and mortality in both sexes. Treatment includes enzyme replacement therapies (ERTs) and chaperone therapy. A better understanding of this disorder from its diagnostic journey, along with the impact of patient characteristics and available treatments on disease prognosis are relevant topics for physicians dealing with FD. The Global buRden and treatment trajectOries in Italian patients with Fabry disease: a retrospective longitUdinal and cross-sectioNal study–GROUND describes a cohort of FD Italian patients, addressing the unmet needs arising from this condition while providing a real-world picture from which further research insights can be derived.

Methods
This was a retrospective, longitudinal and cross-sectional study. Data about adult patients of either sex living or deceased with a documented FD diagnosis and at least 3 years of follow-up or early occurrence of severe/fatal outcomes were collected. Occurrence of severe/fatal events (renal, cardiac, cerebral events, death) from birth to last follow-up visit was the composite primary outcome. Other outcomes assessed were disease progression measured by FAbry STabilization indEX (FASTEX), occurrence of clinically significant events/FD related symptoms (i.e., renal function decline, detection/worsening of left ventricular hypertrophy (LVH), lysoGb3 increase, new FD symptoms), time from first manifestation to diagnosis, treatment trajectories.

Results
From June 2021 to June 2022, 199 patients, 73 males and 126 females, including 169 classic and 30 late-onset phenotypes, were enrolled at 8 Italian centers. Median time from onset of FD symptoms to diagnosis was 60.3 months [95% confidence interval (IC) 38.8-89.7], with a median of 0.64 years (range 0-19.29) from diagnosis to beginning of treatment. Chronic pain and angiokeratomas were the most common initial symptoms (18.1% and 13.1% of patients respectively); acroparesthesia and abdominal pain were reported in 12.5% of patients and LVH in 8.5%. Among the 143 missense/nonsense mutations identified, 14 were Variants of Uncertain Significance (VUS). Overall, 82% of patients were treated with 1 FD specific therapy, of whom 24% switched at least one treatment, while 5% definitively stopped. The composite primary outcome was experienced by 31.7% of patients for a total of 85 severe/fatal events. Specifically, 7.5% (n = 15, all treated) patients experienced a renal event; 20.6% of patients had a cardiac event (n = 41, 38/41 treated); 11.1% (n = 22, all but 1 treated) of subjects experienced a cerebral event; fatal events occurred in 7 patients of whom 1 was untreated. In addition, 88.9% of patients reported at least one clinically significant event, among which detection/worsening of LVH was the most common (41.2%). Estimated Glomerular Filtration rate (eGFR) slopes in the last 1-3 years of follow up were −2.07 [Standard Error (SE): 1.38] and −0.76 (SE: 1.75) in classic males and females, respectively. Long-term (i.e., from diagnosis to last available measure) FASTEX identified 31.1% of patients as being unstable.

Conclusions
In this real-world Italian FD cohort, patients were promptly treated after diagnosis according to existing guidelines, following expert evaluation. Nevertheless, severe clinical events occurred in about 30% of the cohort, mainly among classic treated males, revealing persistent unmet needs such as a better assessment of determinants of disease progression and outcomes, as well as response to treatment and further insights on the potential benefit of new therapeutic options.