Newborn Screening for Fabry Disease: Current Status of Knowledge

Abstract

Fabry disease is an X-linked progressive lysosomal disorder, due to α-galactosidase A deficiency. Patients with a classic phenotype usually present in childhood as a multisystemic disease. Patients presenting with the later onset subtypes have cardiac, renal and neurological involvements in adulthood. Unfortunately, the diagnosis is often delayed until the organ damage is already irreversibly severe, making specific treatments less efficacious. For this reason, in the last two decades, newborn screening has been implemented to allow early diagnosis and treatment. This became possible with the application of the standard enzymology fluorometric method to dried blood spots. Then, high-throughput multiplexable assays, such as digital microfluidics and tandem mass spectrometry, were developed. Recently DNA-based methods have been applied to newborn screening in some countries. Using these methods, several newborn screening pilot studies and programs have been implemented worldwide. However, several concerns persist, and newborn screening for Fabry disease is still not universally accepted. In particular, enzyme-based methods miss a relevant number of affected females. Moreover, ethical issues are due to the large number of infants with later onset forms or variants of uncertain significance. Long term follow-up of individuals detected by newborn screening will improve our knowledge about the natural history of the disease, the phenotype prediction and the patients’ management, allowing a better evaluation of risks and benefits of the newborn screening for Fabry disease.

Light and Shadows in Newborn Screening for Lysosomal Storage Disorders: Eight Years of Experience in Northeast Italy

“…The two female newborns were found to be false positives (overall PPV 90%). The overall incidence of α-GalA deficiency was 1:8879 (1:4121 males), which is similar to previous reports from NBS programs [59], but higher than the clinically estimated incidence (1:40,000) [60], probably due to the recognition of previously undiagnosed later-onset forms of FD. Ten patients carried unclassified variants.…”

“…In the USA, FD is not included in the RUSP, but local laws promoted by NBS advocates and parents allowed its implementation in NBS in several states. These programs confirmed the high incidence of the disease (1:1790 to 1:15,558), but also the high number of false positives [ 59 ]. Conversely, in Taiwan, NBS for FD was started in 2006.…”

“…Our results demonstrate that biochemical 2TTs are effective in reducing the recall rate for MPS I (GAG quantification) and GD (LysoGb1). In FD, the use of LysoGb3 in the neonatal period is debated [ 59 ]. The development of a 2TT is important for all the screened diseases.…”

Detection of α-Galactosidase A Reaction in Samples Extracted from Dried Blood Spots Using Ion-Sensitive Field Effect Transistors

“…Recently, pilot NBS programs for Fabry disease (FD) have been implemented worldwide to explore the potential inclusion of this disease in national programs in Europe [ 2 , 3 ], Japan [ 4 ], China [ 5 ], and the USA [ 6 ]. These results have shown that FD is surprisingly more common than previously considered [ 7 ]. FD is associated with lysosomal glycohydrolase α-galactosidase A (GLA) deficiency, which causes premature death due to cardiovascular disease, kidney failure, and strokes, if not treated from birth with the recommended enzyme replacement therapy [ 8 , 9 ].…”

“…FD is associated with lysosomal glycohydrolase α-galactosidase A (GLA) deficiency, which causes premature death due to cardiovascular disease, kidney failure, and strokes, if not treated from birth with the recommended enzyme replacement therapy [ 8 , 9 ]. The methods used for pilot NBS programs for FD are based on fluorometry, digital microfluidics, tandem mass spectrometry, and immune quantification and are discussed in detail in the review by Gragnianiello and colleagues [ 7 ]. However, despite the variety of methods currently available for the diagnosis of this disease, for the widespread dissemination of newborn screening, it is necessary to improve the cost of analysis, accuracy, parallelism, and extraction of information from a limited amount of biological material.…”