Characterisation and Treatment of Fabry’s Disease in Female Pediatric Patients

Background: Fabry disease (FD) is the second most frequent lysosomal storage disorder worldwide. It is an X-linked genetic disease caused by pathogenic variants in the GLA gene responsible for encoding the alpha-galactosidase enzyme (α-Gal A) involved in glycosphingolipid metabolism. This is a progressive and systemic condition that affects both males and females. The phenotypic spectrum of female patients is heterogeneous depending on the type of variants of the GLA gene, the level of residual α-Gal, and the pattern of X-chromosome inactivation (lyonization), ranging from asymptomatic patients to a severe phenotype as in classic males. Complications are also common in female patients, including kidney failure, hypertrophic cardiomyopathy, cerebrovascular accidents, and premature death. This article approaches relevant aspects for understanding the pathology and highlights the importance of comprehensive and frequent monitoring of women with FD, vital to ensure that patients can benefit from early treatment to prevent irreversible organ damage, improve quality of life, and reduce the impact and morbidity/mortality.

Methods and materials: A systematic review of English and Spanish scientific reference articles in FD regarding female pediatric patients published from 2019 to 2022 in the databases: PUBMED, SCIENCIDIRET, GOOGLE and Clinical Trials was performed. The databases were searched using the keywords: Fabry disease, Sphingolipidosis, X Chromosome Inactivation, heterozygous females, GLA gene, lysosomal storage diseases and Inborn Errors of metabolism.

Results: Currently, treatment options include recombinant enzyme replacement therapy (ERT) with intravenous agalsidase-alfa or agalsidase-beta every 2 weeks. Two new forms of ERT have been developed: Pegunigalsidase-alfa (PRX-102) and moss-agalactosidase A (moss-aGal) with increased stability and lower immunogenicity. Oral chaperone therapy with migalastat selectively and reversibly binds to the active site of GAL, thereby correcting the misfolding of the enzyme and allowing it to traffic to the lysosome. It was approved for female patients with an amenable variant, starting at age 12 and weighing at least 45 kilograms. Additional oral therapy is represented by substrate reduction therapy (SRT) developed Venglustat and Lucerastat, which act by inhibiting glucosylceramide synthase (GSC), thereby reducing the accumulation of Gb3 and lysoGb3 in cells of the heart and kidney. SRT is only available in clinical studies, and it is not currently licensed for treatment. A promising option for treatment in the future is gene therapy. The advantages of using viral vectors, such as adenoviruses and lentiviruses, include that they can directly correct gene defects and their durable efficacy. A Phase 2 clinical trial is ongoing to assess the efficacy and safety of AVR-RD-01, a gene therapy based on an adenovirus encoding GLA cDNA administrated for cellular expression of α-Gal A in different organs; this study is now open to female patients. Nonviral treatment modalities include siRNA, mRNA, and naked plasmid DNA. Compared to viral vectors, non-viral vectors have substantially less toxicity and immunogenicity. Administration of mRNA increased α-Gal A levels expressed in different tissues (kidney, liver, heart), however, it has a transient effect requiring repeated administration.

Conclusion: Delays in diagnosis contribute to high morbidity/mortality and reduced life expectancy due to this disease, which should be more well-known by health professionals. Pedigree analysis can help identify female patients at an earlier age. Diagnostic confirmation in female patients requires molecular genetic detection of causal variants but once the diagnosis is made, it is possible to change the disease’s natural history and progression as well as to improve the patient’s quality of life using currently available and potential future targeted therapies and offering genetic counselling.