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Special Issue Introduction

Fabry disease (FD) is secondary to pathogenic variants of the GLA gene leading to total or partial deficiency
of the lysosomal enzyme alpha-galactosidase (AGAL) with the consequence of accumulation of the lipid
substrate globotriaosylceramide (Gb3) and its active deacetylated metabolite, globotriaosylsphingosine
(Lyso-Gb3). Around 1,000 GLA gene variants have been reported in association with a broad genotype-
phenotype correlation with classical and late-onset presentations.

One of the persisting problems over the years is the delayed diagnosis, probably influenced by unspecific
early clinical manifestations. The natural course of the disease is a continuum progression where the
lysosomal storage leads to a lysosomal dysfunction, cellular damage, and a consequent later organ damage.
Early diagnosis relies on biomarkers, but in FD, there is a lack of a definitive biomarker strongly related
to the disease burden. Early identification of clinical events, together with biomarkers indicating cellular
and organ damage, is crucial to initiating timely and effective treatment. Over the past 20 years, enzyme
replacement therapy (ERT) with recombinant AGAL (agalsidase alfa and beta) has been the most extensively
utilized treatment. More recently, other therapies such as the chaperone Migalastat and Pegunigalsidase
alfa have been approved. Substrate reduction therapy (Lucerastat, Venglustat) is still under clinical trial
evaluation, as are some types of genetic therapies. ERT may trigger an immunological reaction, resulting in
the production of anti-drug antibodies (ADAs) in a high proportion of patients. Fortunately, personalized and
precision treatments are on the horizon for FD patients, though several unmet needs still remain.

We welcome you to this significant Special Issue on Fabry disease! Our objective is to gather the latest
advancements in Diagnosis and Treatment, inviting manuscripts that cover a wide range of relevant topics.
Join us as we delve into the ambiguities of GLA gene variant interpretation and unravel the complexities
of this condition. Discover the unique clinical characteristics of Pediatric Fabry and explore the diverse
perspectives of both male and female patients. Journey through the realm of patient registries and outcome
measures, shedding light on the impact of Fabry disease. Gain insights into the varying degrees of severity
of Fabry disease, providing a deeper understanding of this condition. Explore the importance of early
diagnosis and screening in high-risk populations, extending the scope to include family studies and Newborn
Screening (NBS). Uncover the potential of biomarkers such as Lyso-Gb3 and explore new biomarkers that
contribute to our knowledge of Fabry disease. Dive into the intricacies of kidney function, albuminuria/
proteinuria, and the role of podocytes. Investigate Fabry cardiomyopathy, studying the impact of storage,
inflammation, and fibrosis, and utilizing cardiac magnetic resonance imaging for better diagnosis. Explore
the connections between Fabry disease, stroke, and transient ischemic attacks (TIA). Gain a deeper
understanding of peripheral neuropathy and pain in Fabry disease. Explore the current and future treatment
options that hold promise for managing Fabry disease. Lastly, understand the impact of Fabry disease on the
quality of life, highlighting the importance of holistic care. Embark on this enlightening journey with us as
we uncover new insights and advance our knowledge of Fabry disease for the benefit of patients worldwide.