Fabry disease (FD) is a rare X-linked glycosphingolipidosis caused by mutations in GLA, a gene responsible for encoding α-galactosidase A, an enzyme required for degradation of glycosphingolipids, mainly globotriaosylceramide (Gb3) in all cells of the body. FD patients present a broad spectrum of clinical phenotype and many symptoms are shared with other diseases, making diagnosis challenging. Here we describe a novel GLA variant located in the 5′ splice site of the intron 3, in four members of a family with neuropsychiatric symptoms. Analysis of the RNA showed the variant promotes alteration of the wild type donor site, affecting splicing and producing two aberrant transcripts. The functional characterization showed absence of enzymatic activity in cells expressing both transcripts, confirming their pathogenicity. The family presents mild signs of FD, as angiokeratoma, cornea verticillata, acroparesthesia, tinnitus, vertigo, as well as accumulation of plasma lyso-Gb3 and urinary Gb3. Interestingly, the man and two women present psychiatric symptoms, as depression or schizophrenia. Although psychiatric illnesses, especially depression, are frequently reported in patients with FD and studies have shown that the hippocampus is an affected brain structure in these patients, it is not clear whether the Gb3 accumulation in the brain is responsible for these symptoms or they are secondary. Therefore, new studies are needed to understand whether the accumulation of Gb3 could produce neuronal alterations leading to psychiatric symptoms.

法布里病 (FD) 是一种罕见的 X 连锁糖鞘脂病，由GLA突变引起，GLA 是一种负责编码 α-半乳糖苷酶 A 的基因，这是一种降解糖鞘脂所需的酶，主要是身体所有细胞中的球三糖基神经酰胺 (Gb3)。FD 患者表现出广泛的临床表型，并且许多症状与其他疾病相同，这使得诊断具有挑战性。在这里，我们描述了一种新颖的GLA位于内含子 3 的 5' 剪接位点的变体，存在于具有神经精神症状的家族的四个成员中。RNA 分析表明，该变体促进了野生型供体位点的改变，影响了剪接并产生了两个异常转录本。功能表征显示在表达两种转录物的细胞中不存在酶活性，证实了它们的致病性。该家族表现出轻微的 FD 迹象，如血管角化瘤、角膜轮状瘤、感觉异常、耳鸣、眩晕，以及血浆溶血 Gb3 和尿 Gb3 的积累。有趣的是，该男子和两名妇女出现了精神症状，如抑郁症或精神分裂症。虽然精神疾病，尤其是抑郁症，在 FD 患者中经常报道，并且研究表明海马体是这些患者受影响的大脑结构，目前尚不清楚大脑中的 Gb3 积累是导致这些症状的原因还是继发性的。因此，需要新的研究来了解 Gb3 的积累是否会产生导致精神症状的神经元改变。