Globotriaosylsphingosine (lyso-Gb3) might not be a reliable marker for monitoring the long-term therapeutic outcomes of enzyme replacement therapy for late-onset Fabry patients with the Chinese hotspot mutation (IVS4+919G>A)

Abstract

BackgroundIn Taiwan, DNA-based newborn screening showed a surprisingly high incidence (1/875 in males and 1/399 in females) of a cardiac Fabry mutation (IVS4 + 919G > A). However, the natural course, long-term treatment outcomes and suitable biomarkers for monitoring the therapeutic outcomes of these patients are largely unknown.MethodsFabry disease (FD) patients who had received enzyme replacement therapy (ERT) for more than 1 year were enrolled in this study from December 2008 to April 2013. Periodic echocardiography and serum globotriaosylsphingosine (lyso-Gb3) analysis were carried out. Before and after ERT, left ventricular mass index (LVMI) and serum lyso-Gb3 level were compared and the correlation between the change of LVMI and the change of serum lyso-Gb3 were also analyzed.ResultsThirty-six patients, in four patient groups, were enrolled: (1) 16 males with IVS4 + 919G > A mutation; (2) 7 females with IVS4 + 919G > A mutation; (3) 2 males with classical mutations; and (4) 11 females with classical mutations. The follow-up period was 13–46 months. There were significant LVMI reductions after ERT in all four groups after excluding confounding factors. However, interestingly, serum lyso-Gb3 decreased significantly in the early period after ERT in all groups, but increased gradually after an average of 11.1 months after ERT in late-onset male and female Fabry groups, even when their LVMI still decreased or remained stable. Furthermore, there was no correlation between the change of serum lyso-Gb3 and the change of LVMI in both classical and IVS4 + 919G > A FD patients.ConclusionAlthough lyso-Gb3 has a high diagnostic sensitivity in late-onset Fabry patients and has a good response to ERT during the early stages, it might not be a reliable marker for monitoring the long-term therapeutic outcomes of ERT for late-onset Fabry patients with the Chinese hotspot mutation (IVS4 + 919G > A).

Prevalence and clinical features of Fabry disease in Japanese male patients with diagnosis of hypertrophic cardiomyopathy

“…However, the patient with IVS+919G>A mutation in our study showed undetectable level of lyso-Gb3, and Liu et al reported that lyso-Gb3 might not be a reliable biomarker for monitoring the long-term therapeutic outcomes of ERT for late-onset FD patients with the same mutation (IVS+919G>A) [14]. Recently a highsensitive assay method for measuring lyso-Gb3 in clinical samples by means of nano-liquid chromatography-tandem mass spectrometry has been developed, and it enables us to determine low level of plasma lyso-Gb3 concentration [27].…”

“…There was no typical pathology of FD from a skin biopsy, and his plasma lyso-Gb3 level was below the detection level (<2 nmol/l) and it could not be differentiated from the normal controls. However, genetic analysis revealed an intronic mutation (IVS4+919G>A) that is known to be a Chinese hot spot mutation causing late-onset variant of FD with cardiac hypertrophy in Taiwan [13,14]. He was finally diagnosed as having advanced stage of a cardiac variant FD.…”

Long-Term Dose-Dependent Agalsidase Effects on Kidney Histology in Fabry Disease

“…LysoGb3 was increased in all patients; however, true baseline levels were only available for five patients. A considerable drop was seen in the five patients with true baseline values, in line with earlier studies (34,35). The most prominent agalsidase effect on lysoGb3 can be found during the first year of treatment (35).…”

Cryptogenic stroke and small fiber neuropathy of unknown etiology in patients with alpha-galactosidase A-10T genotype

“…In contrast to mutations in coding regions affecting peptide sequences and possibly modifying protein structure and function, the consequences of intronic sequences are not predictable. As shown for the mid-intronic GLA mutation IVS4+919A>G, intronic variations can affect the process of alternative splicing [ 7 , 8 ]. Due to this mutation, a weak splice site can be converted, resulting in an increased recognition and the insertion of an intronic sequence into the GLA transcript leading to a cardiac phenotype of FD [ 7 , 8 ].…”