La Russa Antonella, Siniscalchi Antonio, Bonaventura Ardito, Di Noia Domenico, Valsania Teresa, Stallone Giovanni, Tartaglia Luciano, Chiapparino Concetta, Di Rienzo Giovanni, Coppolino Giuseppe, Bolignano Davide, Faga Teresa, Michael Ashour, Montesanto Alberto, Serra Raffaele, Andreucci Michele
Nephrology Unit, Department of Health Sciences, "Magna Graecia" University, I-88100 Catanzaro, Italy.
Department of Neurology and Stroke Unit, Annunziata Hospital, I-87100 Cosenza, Italy.
Int J Mol Sci. 2025 May 6;26(9):4400. doi: 10.3390/ijms26094400.
Anderson Fabry disease (AFD) is an X-linked hereditary lysosomal abnormality that causes the accumulation of glycosphingolipids in body fluids and tissues, leading to progressive organ damage and a shortened life span. More than 1000 mutations in the gene have been identified, promoting many different clinical pictures. For this reason, diagnosing AFD can be difficult, especially because of the great diversity of atypical clinical presentations that can simulate the disease. Some of these variants of the gene have been described as non-pathogenic. For example, the D313Y variant is one of the most controversial, even if there are several case reports of D313Y patients presenting with signs and symptoms consistent with AFD without any other etiological explanation. This work aimed to clarify whether the presence of the D313Y variant affects α-Gal A activity and causes AFD symptoms and organ involvement in two patients from different families. The presence of the D313Y variant resulted in clinical manifestations of AFD in both patients and a decrease in alpha-galactosidase activity in the male patient. Two patients (one female and one male) from two unrelated families were examined. Sequencing of all seven exons and the adjacent 5' and 3' exon-intron boundaries identified the D313Y variant in exon 6, as well as the genetic variation g.1170C>T in the flanking 5' UTR in patient 1 only. Our results suggest that the D313Y variant is causative for the disease and that the clinical phenotype can be enhanced by the presence of other variants modulating protein expression.
安德森法布里病（AFD）是一种X连锁遗传性溶酶体异常疾病，可导致糖鞘脂在体液和组织中蓄积，进而引起进行性器官损害并缩短寿命。该基因已鉴定出1000多个突变，导致多种不同的临床表现。因此，诊断AFD可能具有挑战性，尤其是因为非典型临床表现的多样性极大，可能会误诊该疾病。该基因的一些变异已被描述为无致病性。例如，D313Y变异是最具争议的变异之一，尽管有几例D313Y患者的病例报告显示其出现了与AFD一致的体征和症状，且无任何其他病因解释。这项研究旨在阐明D313Y变异的存在是否会影响α - 半乳糖苷酶A（α-Gal A）的活性，并导致来自不同家庭的两名患者出现AFD症状和器官受累情况。D313Y变异的存在导致两名患者均出现AFD临床表现，且男性患者的α - 半乳糖苷酶活性降低。研究检查了来自两个无亲缘关系家庭的两名患者（一名女性和一名男性）。对所有七个外显子以及相邻的5'和3'外显子 - 内含子边界进行测序，在6号外显子中鉴定出D313Y变异，仅在患者1的侧翼5'非翻译区（UTR）中发现了基因变异g.1170C>T。我们的结果表明，D313Y变异是该疾病的病因，并且其他调节蛋白表达的变异的存在可能会加重临床表型。
