SCREENING DIAGNOSTICS OF FABRIC DISEASE AMONG PATIENTS WITH CHRONIC KIDNEY DISEASE IN THE NORTH-WESTERN REGION OF RUSSIA

Fabry disease (FD) is a progressive multi-organ disease leading to the development of cardiovascular and cerebrovascular complications and progression of renal failure. Nonspecificity of clinical signs often leads to late diagnosis of the FD that causes high diagnostic relevance of screening in high risk groups, particularly among patients with chronic kidney disease (CKD). According to the results of screening programs in many countries, the average prevalence of FD among patients with CKD is about 0.26%. THE AIM of this study was to investigate the prevalence of FD in patients with CKD in the northern west region of Russian Federation. PATIENTS AND METHODS. This prospective study assessed α-galactosidase A (α-Gal A) activity in dried blood spots in 1835 stage 1-5 CKD (85% – dialysis, 15% – pre-dialysis) patients, 74% males, mean age 55±12 years. The survey was carried out regardless of gender, age and primary diagnosis leading to CKD. The activity of α-Gal A more than 1.89 umol/l/hr was considered as normal. In the case of identifying the decreased activity of the enzyme the diagnosis was confirmed by GLA gene mutation analysis. RESULTS. The average level of α-Gal A was 5.39±2.69 umol/l/h. The level of α-Gal A was significantly higher in patients with pre-dialysis stages of CKD compared with patients receiving dialysis (7.5±3 vs 4.3±2.3 umol/l/h, p<0.001) as well as in males higher than in females (5.9±3.4 vs 3.4±2.3 umol/l/h, p <0.001). The decrease in α-Gal A activity was detected in 6 patients, of which 3 had the GLA gene mutations (c.427G>A, с.818Т>С, c.895G>C). One patient (p.508G> T) had a confirmed FD and received an enzyme-replacement therapy at the time of screening. All patients with identified FD were males treated by hemodialysis. Thus, the prevalence of FD in patients with CKD C5d was 1:392 (0.26%). A survey of relatives revealed the disease in two additional cases. CONCLUSION. The prevalence of Fabry disease in selected CKD patients of northern west region of Russian Federation is in the mean worldwide range. In all cases, the FD was not timely diagnosed, leading to serious organ damage and delaying the onset of enzyme replacement therapy. Thus, the screening of FD is necessary at the early stages of CKD.

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MO061IS THE PM290I MUTATION RELATED TO ORGAN INVOLVEMENT OF FABRY DISEASE?

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfab080.0033 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

Francisca Silva ◽

Nicole Pestana ◽

José Durães ◽

Nuno Guimarães Rosa ◽

Gil Silva

Keyword(s):

Enzyme Replacement Therapy ◽

Fabry Disease ◽

Replacement Therapy ◽

Genetic Variant ◽

Clinical Manifestations ◽

Mutant Enzyme ◽

Enzyme Replacement ◽

Screening Study ◽

Gla Gene

Abstract Background and Aims Fabry disease (FD) is an X-linked hereditary disease. It results from mutations in the GLA gene, leading to deficient activity of the enzyme alpha-galactosidase A and progressive accumulation of undegraded glycosphingolipids in cell lysosomes. Enzyme replacement therapy improved the natural course of this disease, but an early diagnosis is crucial for a successful treatment. Method A screening study for GLA gene mutations was conducted for all patients under dialysis, from a single centre. All the probands with a detectable mutation were analysed individually. Data on the patient's family and personal pathological history were retrospectively collected, by consulting the clinical file. Results 35 years-old female diagnosed with chronic proteinuric kidney disease in the postpartum period. Despite optimal medical treatment the disease progressed, and she started renal replacement therapy with peritoneal dialysis. Five years later she was enrolled in a pilot screening study for FD and the heterozygous mutation c.870G>C (p.Met290Ile; M290I) in exon 6 of the GLA gene was found. The proband didn’t meet the criteria for a definitive FD diagnosis, but she remained under follow-up at our nephrology metabolic diseases consultation, as the mutation was described as pathogenic and associated with a classic FD phenotype. Later that same year, reassessment exams revealed a worsening left ventricle mass index, a new ischemic cerebral lesion and a substantial increase in serum globotriaosylsphingosine (LysoGb3) levels. These clinical changes led to the decision to initiate enzyme replacement therapy. Until now there are only a few descriptions of this genetic variant in the scientific literature. A Portuguese study analysed a total of 11 FD patients and described 2 patients with p.M290I mutation, without detectable Gb3 accumulation. Another study was designed to evaluate the genotype-phenotype relationship in 73 Chinese FD patients. Contrary to other reports, the p.M290I mutation was not associated to the classic FD phenotype. A Swiss investigation with a similar design analysed 69 FD patients during their routine annual examinations. M290I mutant enzyme was found in a 48-year-old heterozygous female with a classic FD phenotype but with a low serum LysoGb3. A Spanish newborn screening identified one male patient with FD and the p.M290I genetic variant but was unable to provide any information about the clinical expression of this mutation, since the diagnosis was made between the third and fifth days of life. The study describing the most patients carrying the M290I mutant enzyme is Brazilian and screened a total of 25,223 dialysis patients. Among 89 FD-positive patients, the p.M290I mutation was present in 22. However, the authors did not provide detailed information about the clinical manifestations or α-Gal A activity and LysoGb3 levels of these patients. Finally, a recent Portuguese screening of 150 hypertrophic cardiomyopathy patients found 25 patients with FD. Of these, one female carried the GLA gene variant p.M290I, with a non-detectable LysoGb3 plasma level. Conclusion We describe a case of FD due to a previously known but still poorly described GLA mutation, which offers strong evidence of its pathogenicity. To our knowledge, this is the first report of p.M290I mutation-associated disease activity evidenced by elevated levels of serum LysoGb3. Despite the absence of classic FD symptoms such as neuropathic pain, cornea verticillata and angiokeratoma, the presence of severe multiple organ evolvement, characterized by renal failure, cardiac disease and ischaemic stroke, strongly suggests a classic phenotype. Consequently, it is our opinion that the presence of a p.M290I GLA mutation should require a strict ongoing patient follow-up, as it may cause clinically significant disease.

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Mulberry bodies in the urine sediment of a patient with chronic kidney disease

Advances in Laboratory Medicine / Avances en Medicina de Laboratorio ◽

10.1515/almed-2020-0028 ◽

2020 ◽

Vol 1 (3) ◽

Author(s):

Carlos Martínez-Figueroa ◽

Karen Cortés-Sarabia ◽

Hilda Guadalupe Catalán-Nájera ◽

Micaela Martínez-Alarcón

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Fabry Disease ◽

Hereditary Disease ◽

Urine Sediment ◽

Enzyme Replacement ◽

Laboratory Test Results ◽

Organic Dysfunction ◽

History Of ◽

Gla Gene

AbstractObjectivesFabry disease is a hereditary disease caused by a mutation in the α-galactosidase A (GLA) gene resulting in the accumulation of glycosphingolipids in different organs. Timely diagnosis is crucial for the early initiation of treatment to avoid organic dysfunction secondary to lipid accumulation. In view of the above, a number of studies have been performed to assess the role of mulberry bodies as a new diagnostic tool. In this study, we report a case demonstrating the utility of this test.Case presentationWe report the case of a woman of advanced age without a history of chronic disease with symptoms consistent with urinary tract infection (dysuria, pelvic pain, and frequent urination). Based on laboratory test results, a diagnosis of anemia with concomitant chronic kidney disease was established. Urine test revealed microhematuria, proteinuria, urine sediment, and the presence of lipid particles consistent with mulberry bodies.ConclusionsThe identification of mulberry bodies and cells in urine sediment is an easy-to-use tool potentially useful in diagnosing Fabry disease, which may contribute to initiate enzyme replacement therapy in a timely manner and reduce systemic deterioration.

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Fabry disease due to G171S GLA mutation: An atypical small nerve fiber sparing variant?

European Journal of Ophthalmology ◽

10.1177/1120672120939496 ◽

2020 ◽

pp. 112067212093949

Author(s):

Matteo Prencipe ◽

Chiara Posarelli ◽

Michele Figus ◽

Giovanna Gabbriellini

Keyword(s):

Enzyme Replacement Therapy ◽

Fabry Disease ◽

Replacement Therapy ◽

Nerve Fiber ◽

Enzyme Replacement ◽

Ocular Manifestations ◽

Cornea Verticillata ◽

Gla Gene ◽

Small Nerve

Introduction: To describe the ocular manifestations and in vivo confocal microscopic findings in a patient carrying the recently described hemizygous G171S GLA gene mutation. Case description: A 63-year-old Albanian male patient was evaluated for cataract surgery. Anamnesis showed pacemaker implantation in left ventricular hypertrophy, chronic kidney disease, family history for kidney transplantation, and late onset of sporadic acroparesthesias. Bilateral cornea verticillata, and increased tortuosity in conjunctival and retinal vessels were present. In vivo confocal microscopy revealed clusters of hyper-reflective corneal epithelial cells centripetally extending from the limbus. Interestingly, the nerve fiber number, density, and length in the corneal sub-basal nerve plexus were preserved. Alpha-galactosidase A activity was almost absent and hemizygous c.511G>A mutation (G171S – p.Gly171Ser) of the GLA gene was identified. The patient was referred for initiation of enzyme replacement therapy, and genetic counseling was recommended for at-risk family members. Conclusion: This is the third reported case of Fabry disease due to GLA G171S mutation. All patients are of Albanian descent. Cornea verticillata and vascular anomalies remain common ocular manifestations, as well as cardiac and renal involvement. Confirming its pathogenicity, this mutation results in a “classic” Fabry disease phenotype, but it seems to be associated with a relative small nerve fiber sparing that may delay a correct diagnosis. The diagnosis of Fabry disease still remains challenging due to its clinical heterogeneity, but a thorough ophthalmological examination can promote early detection and, consequently, early initiation of enzyme replacement therapy.

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Diurnal Variation of Urinary Fabry Disease Biomarkers during Enzyme Replacement Therapy Cycles

International Journal of Molecular Sciences ◽

10.3390/ijms21176114 ◽

2020 ◽

Vol 21 (17) ◽

pp. 6114

Author(s):

Michel Boutin ◽

Pamela Lavoie ◽

Iskren Menkovic ◽

Amanda Toupin ◽

Mona Abaoui ◽

...

Keyword(s):

Enzyme Replacement Therapy ◽

Fabry Disease ◽

Replacement Therapy ◽

Biological Fluids ◽

Lysosomal Storage ◽

Sample Collection ◽

Gene Encoding ◽

Enzyme Replacement ◽

Sugar Unit ◽

Gla Gene

Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the GLA gene encoding the α-galactosidase A enzyme. This enzyme cleaves the last sugar unit of glycosphingolipids, including globotriaosylceramide (Gb3), globotriaosylsphingosine (lyso-Gb3), and galabiosylceramide (Ga2). Enzyme impairment leads to substrate accumulation in different organs, vascular endothelia, and biological fluids. Enzyme replacement therapy (ERT) is a commonly used treatment. Urinary analysis of Gb3 isoforms (different fatty acid moieties), as well as lyso-Gb3 and its analogues, is a reliable way to monitor treatment. These analogues correspond to lyso-Gb3 with chemical modifications on the sphingosine moiety (−C2H4, −C2H4+O, −H2, −H2+O, +O, +H2O2, and +H2O3). The effects of sample collection time on urinary biomarker levels between ERT cycles were not previously documented. The main objective of this project was to analyze the aforementioned biomarkers in urine samples from seven Fabry disease patients (three treated males, three treated females, and one ERT-naïve male) collected twice a day (morning and evening) for 42 days (three ERT cycles). Except for one participant, our results show that the biomarker levels were generally more elevated in the evening. However, there was less variability in samples collected in the morning. No cyclic variations in biomarker levels were observed between ERT infusions.

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