A classical phenotype of Anderson-Fabry disease in a female patient with intronic mutations of the GLA gene: a case report

Background: Fabry disease (FD) is a hereditary metabolic disorder caused by the partial or total inactivation of a lysosomal hydrolase, the enzyme α-galactosidase A (GLA). This inactivation is responsible for the storage of undegraded glycosphingolipids in the lysosomes with subsequent cellular and microvascular dysfunction. The incidence of disease is estimated at 1:40,000 in the general population, although neonatal screening initiatives have found an unexpectedly high prevalence of genetic alterations, up to 1:3,100, in newborns in Italy, and have identified a surprisingly high frequency of newborn males with genetic alterations (about 1:1,500) in Taiwan. Case presentation: We describe the case of a 40-year-old female patient who presented with transient ischemic attack (TIA), discomfort in her hands, intolerance to cold and heat, severe angina and palpitations, chronic kidney disease. Clinical, biochemical and molecular studies were performed. Conclusions: Reported symptoms, peculiar findings in a renal biopsy – the evidence of occasional lamellar inclusions in podocytes and mesangial cells – and left ventricular (LV) hypertrophy, which are considered to be specific features of FD, as well as molecular evaluations, suggested the diagnosis of a classical form of FD. We detected four mutations in the GLA gene of the patient: -10C>T (g.1170C>T), c.370-77_-81del (g.7188-7192del5), c.640-16A>G (g.10115A>G), c.1000-22C>T (g.10956C>T). These mutations, located in promoter and intronic regulatory regions, have been observed in several patients with manifestations of FD. In our patient clinical picture showed a multisystemic involvement with early onset of symptoms, thus suggesting that these intronic mutations can be found even in patients with classical form of FD

Genetic screening of Fabry patients with EcoTILLING and HRM technology

<p>Abstract</p> <p>Background</p> <p>Anderson-Fabry disease (FD) is caused by a deficit of the α-galactosidase A enzyme which leads to the accumulation of complex sphingolipids, especially globotriaosylceramide (Gb3), in all the cells of the body, causing the onset of a multi-systemic disease with poor prognosis in adulthood. In this article, we describe two alternative methods for screening the <it>GLA </it>gene which codes for the α-galactosidase A enzyme in subjects with probable FD in order to test analysis strategies which include or rely on initial pre-screening.</p> <p>Findings</p> <p>We analyzed 740 samples using EcoTILLING, comparing two mismatch-specific<ul/>endonucleases, CEL I and ENDO-1, while conducting a parallel screening of the same samples using HRM (High Resolution Melting). Afterwards, all samples were subjected to direct sequencing. Overall, we identified 12 different genetic variations: -10C>T, -12G>A, -30G>A, IVS2-76_80del5, D165H, C172Y, IVS4+16A>G, IVS4 +68 A>G, c.718_719delAA, D313Y, IVS6-22C>T, G395A. This was consistent with the high genetic heterogeneity found in FD patients and carriers. All of the mutations were detected by HRM, whereas 17% of the mutations were not found by EcoTILLING. The results obtained by EcoTILLING comparing the CEL I and ENDO-1 endonucleases were perfectly overlapping.</p> <p>Conclusion</p> <p>On the basis of its simplicity, flexibility, repeatability, and sensitivity, we believe that<ul/>HRM analysis of the <it>GLA </it>gene is a reliable presequencing screening tool. This method can be applied to any genomic feature to identify known and unknown genetic alterations, and it is ideal for conducting screening and population studies.</p

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

A pilot study of circulating microRNAs as potential biomarkers of Fabry disease

Patients suffering from Fabry disease (FD), a lysosomal storage disorder, show a broad range of symptoms and the diagnosis followed by the therapeutic decision remains a great challenge. The biomarkers available today have not proven to be useful for predicting the evolution of the disease and for assessing response to therapy in many patients. Here, we used high-throughput microRNA profiling methodology to identify a specific circulating microRNA profile in FD patients. We discovered a pattern of 10 microRNAs able to identify FD patients when compared to healthy controls. Notably, two of these: the miR199a-5p and the miR-126-3p are able to discriminate FDs from the control subjects with left ventricular hypertrophy, a frequent but non-specific FD symptom. These same microRNAs are also sensitive to enzyme replacement therapy showing variation in the subjects under treatment. Furthermore, two other microRNAs of the profile, the miR-423-5p and the miR-451a, seem useful to highlight cardiac involvement in FD patients. A literature and database search revealed that miR-199a-5p, miR-126-3p, miR-423-5p and miR-451a are known to be linked to pathological states that occur during the FD development. In particular, miR-199a-5p, and miR-126-3p are involved in endothelial dysfunction and miR-423- 5p and miR-451a in myocardial remodeling. In conclusion, in this study we identified a common plasma microRNA profile in FD patients, useful not only for the correct classification of Fabry patients regardless of sex and age, but also to evaluate the response to therapy. Furthermore, our observations suggest that some microRNAs of this profile demonstrate prognostic qualities

Cognitive impairment and Fabry Disease: a case report with mutation S126G

Anderson-Fabry Disease is a lysosomal storage disease, multisystem, progressive, hereditary, linked to the X-chromosome. Specifically, it is characterized by a glycosphingolipid metabolism due to the reduction or absence of Alpha-galactosidase, an enzyme activity lisosomile gene mutation GLA (Xq21.3-q22), which encodes the enzyme. The decreased activity causes the accumulation of globotriaosylceramide (Gb3) within lysosomes, which in turn sets off a cascade of cellular events. The clinical picture presents a wide spectrum of manifestations of multiple systems: neurological, skin, kidney, cardiovascular disease, auditory and vestibular and cerebrovascular. Despite the recent interest in the involvement of cognitive studies in literature have not yet produced enough results to outline a possible neuropsychological profile of course. Also, not all researchers agree on the existence of a specific cognitive deficit of Fabry Disease (FD). The case discussed here is a example of a neuropsychological profile in patient with FD (mutation p.S126G)

Novel α-galactosidase A mutation in patients with severe cardiac manifestations of Fabry disease

Fabry disease (FD) is a hereditary metabolic disorder caused by the partial or total inactivation of alpha-galactosidase A (alpha-gal A), a lysosomal hydrolase. This inactivation is responsible for the accumulation of undegraded glycosphingolipids in the lysosomes with subsequent cellular and microvascular dysfunction. Fabry is considered a rare disease, with an incidence of 1:40,000; however, there are good reasons to believe that it is often seen but rarely diagnosed. To date, more than 600 mutations have been identified in human GLA gene that are responsible for FD. We describe the case of a 54-year-old male patient, who presented with left ventricular hypertrophy, chronic renal failure and acroparaesthesias, which are considered to be specific features of FD. Clinical and instrumental investigations showed several cardiovascular manifestations. The molecular analysis of GLA gene revealed a novel mutation in the fifth exon, called N249K, and the enzymatic analysis showed no alpha-galactosidase A activity. Family screening detected the same mutation in some relatives and also the enzymatic analysis confirmed the diagnosis of FD. In conclusion, these data suggest that the N249K mutation may be associated with cardiac manifestations of FD combined with other classical features of the disease. (C) 2013 Elsevier B.V. All rights reserved

Fabry disease, a complex pathology not easy to diagnose

Fabry disease is a multisystemic lysosomal storage disorder, inherited in an X-linked manner. It is a defect of metabolism of the glycosphingolipids, due to the reduction or absence of the activity of lysosomal enzyme α-galactosidase A. This reduction of activity causes the storage of globotriaosylceramide and derivatives in the lysosomes, triggering a cascade of cellular events, mainly in vascular endothelium. These events are the responsible for the systemic clinical manifestations and the renal, cardiac and cerebrovascular complications, or a combination of them. The symptomatology can lead to the premature death of patient between the fourth or fifth decade of life. The first symptoms can occur at different ages, generally in childhood, with different severity and course. Fabry disease is suspected on the basis of clinical and anamnestic-familial data, and it is confirmed by enzymatic and genetic assays. However, Fabry disease could be a pathology more complex than previously considered, and the diagnostic tests that are currently in use could be not always sufficient to confirm the clinical diagnosis. Probably, other factors could be also involved in the onset of symptomatology. In the last years, the knowledge of the disease is considerably increased but other studies are necessary to make a prompt and reliable diagnosis. An early diagnosis of Fabry disease is essential for the beginning of the enzyme replacement therapy, which can contribute to arrest its progression and improve the quality of life of patients