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Page 341 Giliberti et al. J Transl Genet Genom 2024;8:340-54 https://dx.doi.org/10.20517/jtgg.2024.41

particularly globotriaosylceramide (Gb3) and its metabolite globotriaosylsphingosine (lyso-Gb3), in various
[1,2]
cell types, including endothelial cells, cardiomyocytes, peripheral neurons, and renal cells .
FD exhibits a wide range of clinical manifestations influenced by specific mutations in the GLA gene and
gender. Due to its X-linked inheritance, males typically experience more severe symptoms and earlier onset
of complications compared to females .
[3]
FD presents a diverse range of manifestations that progress through different life stages. During childhood
and adolescence, patients typically experience chronic or episodic acroparesthesia, angiokeratomas,
ophthalmologic abnormalities, auditory neuropathy, disorders of sweating, increased albuminuria, and
gastrointestinal disturbances. Young adulthood is marked by more pronounced angiokeratomas, selective
proteinuria, fever, gastrointestinal symptoms, and early-onset cardiac abnormalities. In later adulthood
(> 30 years), individuals often develop severe cardiac complications such as fibrosis, hypertrophy, valve
abnormalities, and dysrhythmias, alongside chronic kidney disease, strokes, and potential hearing loss .
[4,5]

In males, the distinction between “classical” and “non-classical” forms of FD is determined by the residual
activity of α-GAL A enzyme, preferably evaluated in leukocytes, along with the presence of characteristic
clinical manifestations. The classic form of the disease is characterized by negligible or minimal (< 1%)
activity of the α-GalA enzyme, which results in early-onset and widespread multi-organ complications. On
the other hand, the attenuated or later-onset variant appears later in life, with symptoms that vary
depending on the residual levels of α-GalA activity . Heterozygous females exhibit variable clinical
[6]
manifestations, and enzyme activity alone does not consistently distinguish between different phenotypes. It
is hypothesized that severe disease in females heterozygous for an X-linked disorder results from
unfavorable skewing during Lyonization, leading to biased inactivation of the wild-type allele in the
majority of tissues. As a result, in females, classification relies on genetic mutation analysis, family history,
and comprehensive clinical and biochemical evaluations .
[7]
Current therapeutic strategies for FD include enzyme replacement therapy (ERT) and oral chaperone
treatment. The ERT category includes agalsidase α, agalsidase β and pegunigalsidase α, recombinant α-Gal A
[8,9]
proteins that are effective in symptom control and in decelerating or arresting disease progression .
Chaperone therapy with Migalastat works by stabilizing the residual endogenous enzyme, correcting its
[10]
misfolding, and thereby restoring the degradation of glycolipids . Numerous other molecules are currently
[11]
under investigation . A novel form of ERT, moss-αGal, derived from plants has been shown to be effective,
safe, and well-tolerated in early studies so far .
[12]
An additional therapeutic strategy involves substrate reduction therapy (SRT), which is designed to
attenuate the production of metabolic products that cannot be degraded due to the inherent enzymatic
deficiency. In this context, Venglustat and Lucerastat inhibit glucosylceramide synthase (GCS) to limit the
amount of metabolites not degradable due to the lack of α-GalA enzyme [13,14] .

Further advancements in therapeutic approaches for FD are represented by gene therapy. This strategy is
designed to direct the therapy toward circulating hematopoietic cells using a recombinant vector capable of
transducing and correcting the target cells. These cells would then acquire the ability to produce significant
amounts of α-galactosidase A, both intracellularly and in their secretions [15,16] .

Beyond genetic interventions, systemic messenger RNA (mRNA)-based therapeutics are under
development for FD. This approach aims to enhance endogenous protein synthesis, thereby improving the