Abstract
Enzyme replacement therapy (ERT) is a mainstay of treatment for Anderson–Fabry disease (AFD), a pathology with negative effects on the heart and kidneys. However, no reliable biomarkers are available to monitor its efficacy. Therefore, we tested a panel of four microRNAs linked with cardiac and renal damage in order to identify a novel biomarker associated with AFD and modulated by ERT. To this end, 60 patients with a definite diagnosis of AFD and on chronic ERT, and 29 age- and sex-matched healthy individuals, were enrolled by two Italian university hospitals. Only miR-184 met both conditions: its level discriminated untreated AFD patients from healthy individuals (c-statistic = 0.7522), and it was upregulated upon ERT (P < 0.001). On multivariable analysis, miR-184 was independently and inversely associated with a higher risk of cardiac damage (odds ratio = 0.86; 95% confidence interval [CI] = 0.76–0.98; P = 0.026). Adding miR-184 to a comprehensive clinical model improved the prediction of cardiac damage in terms of global model fit, calibration, discrimination, and classification accuracy (continuous net reclassification improvement = 0.917, P < 0.001; integrated discrimination improvement [IDI] = 0.105, P = 0.017; relative IDI = 0.221, 95% CI = 0.002–0.356). Thus, miR-184 is a circulating biomarker of AFD that changes after ERT. Assessment of its level in plasma could be clinically valuable in improving the prediction of cardiac damage in AFD patients.
Highlights
Anderson–Fabry disease (AFD) is a rare X-linked lysosomal storage disorder caused by mutations of the alpha-galactosidase A gene (GLA), located on the X chromosome (Xq22.1)
Identification of candidate circulating miRNA biomarkers Four miRNAs were selected as potential biomarkers for AFD due to their role in cardiac and renal damage: hsa-miR-1–3p [42, 43], hsamiR-133a-3p [44, 45], hsa-miR-146a-5p [46], and hsa-miR-184
A pilot screening conducted on a group of patients sampled before and after Enzyme replacement therapy (ERT) administration (N = 12) led to the
Summary
Anderson–Fabry disease (AFD) is a rare X-linked lysosomal storage disorder caused by mutations of the alpha-galactosidase A gene (GLA), located on the X chromosome (Xq22.1). The disease has an early onset, usually in childhood, and its classical phenotype is characterized by neuropathic pain, angiokeratomas, cornea verticillata, and gastrointestinal disturbances [2]; after the third decade of life, cardiac involvement, renal failure, and cerebrovascular events may occur and are the major causes of morbidity and mortality [3]. Non-classical AFD presents with a milder, later onset and a variable phenotype, usually with the manifestation of cardiac disease. As a consequence of random X-chromosome inactivation (lyonization), heterozygous females present with variable clinical manifestations, ranging from an almost absence of symptoms to very severe pathologies similar to those observed in males, albeit usually with a later onset [4]
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