scholarly journals Endocrine disorders in patients with Fabry disease: insights from a reference centre prospective study

Endocrine ◽  
2021 ◽  
Author(s):  
Christina Bothou ◽  
Felix Beuschlein ◽  
Albina Nowak
Keyword(s):  
Prospective Study ◽  
Fabry Disease ◽  
Late Onset ◽  
Density Lipoprotein ◽  
Endocrine System ◽  
Endocrine Disorders ◽  
Enzyme Replacement ◽  
Reference Centre ◽  
Thyroid Screening ◽  
Classic Phenotype

Abstract Context Fabry Disease (FD) is a rare X-linked storage disease characterised by a-galactosidase A deficiency and diffuse organ accumulation of glycosphingolipids. Enzyme replacement and chaperone therapies are only partially effective. It remains unclear if FD-related endocrine disorders contribute to the observed morbidity. Objective To investigate the function of the endocrine system in patients with FD. Design We conducted an observational prospective study from 2017 to 2020. Setting and patients We included 77 patients with genetically confirmed FD (27 men, 20/27 Classic, 7/26 Late Onset phenotype, 50 women, 41/50 and 9/50 respectively), who are systematically followed by our reference centre. Results 36/77 (46.8%) patients had VitD deficiency (25(0H)VitD <20 μg/L) despite the fact that 19/36 (52.8%) were substituted with cholecalciferol. Only 21/77 (27.3%) patients had normal VitD levels without VitD substitution. 11/77 (14.3%) had significant hypophosphatemia (p < 0.80 mmol/L). Three new cases (3.9%) of subclinical, two (2.6%) of overt and six (7.8%) of known hypothyroidism were identified. Of note, men had significantly higher renin levels than women [61.4 (26.1–219.6) vs.25.4 (10.9–48.0) mU/L, p = 0.003]. There were no major abnormalities in adrenal, growth and sex-hormone axes. Patients of Classic phenotype had significantly higher High-Density Lipoprotein Cholesterol (HDL-C) levels (p = 0.002) and in men those levels were positively correlated with globotriaosylsphingosin (Lyso-Gb3) values. 10/77 (13%) of the patients were underweight. Conclusions VitD supplementation should be considered for all patients with FD. Thyroid screening should be routinely performed. Malnutrition should be prevented or treated, particularly in Classic phenotype patients. Overall, our data suggest that FD specialists should actively seek and diagnose endocrine disorders in their patients.

p.G360R Is a Pathogenic GLA Gene Mutation Responsible for a Classic Phenotype of Fabry Disease

Cardiology ◽  
2019 ◽  
Vol 144 (3-4) ◽  
pp. 125-130 ◽  
Author(s):  
Daniela Marisa Carvalho Silva ◽  
Nuno Marques ◽  
Olga Azevedo ◽  
Gabriel Miltenberger-Miltenyi ◽  
Dina Bento ◽  
...  
Keyword(s):  
Left Ventricular Hypertrophy ◽  
Fabry Disease ◽  
Ventricular Hypertrophy ◽  
Left Ventricular ◽  
Gene Variants ◽  
Fabry Patient ◽  
Enzyme Replacement ◽  
Disease Awareness ◽  
Classic Phenotype ◽  
Gla Gene

The authors report the case of a classic phenotype of Fabry disease in a 60-year-old male patient presenting with left ventricular hypertrophy and stroke. Genetic analysis revealed 2 GLA-gene variants, i.e., p.R356Q and p.G360R. This clinical case highlights that the finding of 2 or more GLA gene variants in a Fabry patient should lead to a careful evaluation in order to determine their exact role in the condition. This case also provides the first clinical evidence that the p.G360R mutation is pathogenic and responsible for a classic phenotype of Fabry disease. The clinical improvement following the initiation of enzyme replacement therapy reinforces the importance of Fabry disease awareness and diagnosis in patients exhibiting red flags, such as left ventricular hypertrophy and stroke.

scholarly journals Mutations in the GLA Gene and LysoGb3: Is It Really Anderson-Fabry Disease?

2018 ◽  
Vol 19 (12) ◽  
pp. 3726 ◽  
Author(s):  
Giovanni Duro ◽  
Carmela Zizzo ◽  
Giuseppe Cammarata ◽  
Alessandro Burlina ◽  
Alberto Burlina ◽  
...  
Keyword(s):  
Fabry Disease ◽  
Genetic Variants ◽  
Late Onset ◽  
Clinical History ◽  
Classic Phenotype ◽  
Unknown Significance ◽  
Male Patients ◽  
Alpha Gene ◽  
Reliable Marker ◽  
Gla Gene

Anderson-Fabry disease (FD) is a rare, progressive, multisystem storage disorder caused by the partial or total deficit of the lysosomal enzyme α-galactosidase A (α-Gal A). It is an X-linked, lysosomal enzymopathy due to mutations in the galactosidase alpha gene (GLA), encoding the α-Gal A. To date, more than 900 mutations in this gene have been described. In our laboratories, the study of genetic and enzymatic alterations related to FD was performed in about 17,000 subjects with a symptomatology referable to this disorder. The accumulation of globotriaosylsphingosine (LysoGb3) was determined in blood of positives. Exonic mutations in the GLA gene were detected in 471 patients (207 Probands and 264 relatives): 71.6% of mutations were associated with the classic phenotype, 19.8% were associated with the late-onset phenotype, and 8.6% of genetic variants were of unknown significance (GVUS). The accumulation of LysoGb3 was found in all male patients with a mutation responsible for classic or late-onset FD. LysoGb3 levels were consistent with the type of mutations and the symptomatology of patients. α-Gal A activity in these patients is absent or dramatically reduced. In recent years, confusion about the pathogenicity of some mutations led to an association between non-causative mutations and FD. Our study shows that the identification of FD patients is possible by associating clinical history, GLA gene analysis, α-Gal A assay, and blood accumulation of LysoGB3. In our experience, LysoGB3 can be considered a reliable marker, which is very useful to confirm the diagnosis of Fabry disease.

scholarly journals Effectiveness of immunosuppressive therapy for nephrotic syndrome in a patient with late-onset Fabry disease: a case report and literature review

2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Hironobu Fujisawa ◽  
Yosuke Nakayama ◽  
Shoichiro Nakao ◽  
Ryo Yamamoto ◽  
Yuka Kurokawa ◽  
...  
Keyword(s):  
Nephrotic Syndrome ◽  
Fabry Disease ◽  
Rare Case ◽  
Late Onset ◽  
Immunosuppressive Treatment ◽  
Minimal Change Nephrotic Syndrome ◽  
Genetic Mutation ◽  
Lysosomal Storage ◽  
Enzyme Replacement ◽  
Old Japanese

Abstract Background Fabry disease (FD) is an X-linked lysosomal storage disorder caused by mutations of the GLA gene, followed by deficiency in α-galactosidase A (α-gal) activity. Nephrotic syndrome, as the renal phenotype of FD, is unusual. Here, we report the rare case of a patient with FD with nephrotic syndrome whose proteinuria disappeared by immunotherapy. Case presentation A 67-year-old Japanese man was admitted to our hospital because of emesis, abdominal pain, and facial edema due to nephrotic syndrome. The patient was diagnosed with focal segmental glomerulosclerosis (FSGS) by renal biopsy before being diagnosed with FD, and immunotherapy was initiated. After treatment, the kidney biopsy results showed typical glycosphingolipid accumulation in the podocytes of this patient. The white blood cell α-gal activity was very low, and genetic analysis revealed a GLA gene variant (M296I), which is known as a late-onset genetic mutation of FD. Immunotherapy (steroids and cyclosporine A) dramatically improved the massive proteinuria. Currently, he has been undergoing enzyme replacement therapy, and his proteinuria has further decreased. There is the possibility that other nephrotic syndromes, such as minimal change nephrotic syndrome or FSGS, may co-exist in this patient. Conclusions We experienced the rare case of a FD patient whose nephrotic syndrome disappeared by immunotherapy. These findings suggest that immunosuppressive treatment may be considered if nephrotic syndrome develops, even in patients with FD.

Treatment of Anderson-Fabry Disease

2020 ◽  
Vol 26 (40) ◽  
pp. 5089-5099 ◽  
Author(s):  
Irene Simonetta ◽  
Antonino Tuttolomondo ◽  
Mario Daidone ◽  
Salvatore Miceli ◽  
Antonio Pinto
Keyword(s):  
Fabry Disease ◽  
Treatment Strategies ◽  
Signs And Symptoms ◽  
Current Treatment ◽  
Viral Gene ◽  
Pharmacological Chaperone ◽  
Enzyme Replacement ◽  
Cell Based Therapy ◽  
Organ Manifestations ◽  
Alpha Galactosidase

: Fabry disease is an X-linked disorder of glycosphingolipid metabolism that results in progressive accumulation of neutral glycosphingolipids, predominantly globotriaosylsphingosine (Gb3) in lysosomes, as well as other cellular compartments of several tissues, causing multi-organ manifestations (acroparesthesias, hypohidrosis, angiokeratomas, signs and symptoms of cardiac, renal, cerebrovascular involvement). Pathogenic mutations lead to a deficiency of the lysosomal enzyme alpha-galactosidase A (GLA). In the presence of high clinical suspicion, a careful physical examination and specific laboratory tests are required. Finally, the diagnosis of Fabry’s disease is confirmed by the demonstration of the absence of or reduced alpha-galactosidase A enzyme activity in hemizygous men and gene typing in heterozygous females. Measurement of the biomarkers Gb3 and Lyso Gb3 in biological specimens may facilitate diagnosis. The current treatment of Anderson-Fabry disease is represented by enzyme replacement therapy (ERT) and oral pharmacological chaperone. Future treatments are based on new strategic approaches such as stem cell-based therapy, pharmacological approaches chaperones, mRNA therapy, and viral gene therapy. : This review outlines the current therapeutic approaches and emerging treatment strategies for Anderson-Fabry disease.

scholarly journals Sepsis as a Pan-Endocrine Illness—Endocrine Disorders in Septic Patients

2021 ◽  
Vol 10 (10) ◽  
pp. 2075
Author(s):  
Weronika Wasyluk ◽  
Martyna Wasyluk ◽  
Agnieszka Zwolak
Keyword(s):  
Host Response ◽  
Peripheral Resistance ◽  
Endocrine System ◽  
Endocrine Disorders ◽  
Hormonal Changes ◽  
Adrenergic Stimulation ◽  
Hypothalamic Amenorrhea ◽  
Somatotropic Axis ◽  
Almost All ◽  
Triiodothyronine Concentration

Sepsis is defined as “life-threatening organ dysfunction caused by a dysregulated host response to infection”. One of the elements of dysregulated host response is an endocrine system disorder. Changes in its functioning in the course of sepsis affect almost all hormonal axes. In sepsis, a function disturbance of the hypothalamic–pituitary–adrenal axis has been described, in the range of which the most important seems to be hypercortisolemia in the acute phase. Imbalance in the hypothalamic–pituitary–thyroid axis is also described. The most typical manifestation is a triiodothyronine concentration decrease and reverse triiodothyronine concentration increase. In the somatotropic axis, a change in the secretion pattern of growth hormone and peripheral resistance to this hormone has been described. In the hypothalamic–pituitary–gonadal axis, the reduction in testosterone concentration in men and the stress-induced “hypothalamic amenorrhea” in women have been described. Catecholamine and β-adrenergic stimulation disorders have also been reported. Disorders in the endocrine system are part of the “dysregulated host response to infection”. They may also affect other components of this dysregulated response, such as metabolism. Hormonal changes occurring in the course of sepsis require further research, not only in order to explore their potential significance in therapy, but also due to their promising prognostic value.

scholarly journals High Density Lipoprotein Cholesterol Efflux Capacity and Atherosclerosis in Cardiovascular Disease: Pathophysiological Aspects and Pharmacological Perspectives

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 574
Author(s):  
Maria Pia Adorni ◽  
Nicoletta Ronda ◽  
Franco Bernini ◽  
Francesca Zimetti
Keyword(s):  
High Density Lipoprotein ◽  
Cholesterol Efflux ◽  
Current Knowledge ◽  
Density Lipoprotein ◽  
Hdl Cholesterol ◽  
High Density ◽  
Current Evidence ◽  
Endocrine Disorders ◽  
Lifestyle Modifications ◽  
Cholesterol Efflux Capacity

Over the years, the relationship between high-density lipoprotein (HDL) and atherosclerosis, initially highlighted by the Framingham study, has been revealed to be extremely complex, due to the multiple HDL functions involved in atheroprotection. Among them, HDL cholesterol efflux capacity (CEC), the ability of HDL to promote cell cholesterol efflux from cells, has emerged as a better predictor of cardiovascular (CV) risk compared to merely plasma HDL-cholesterol (HDL-C) levels. HDL CEC is impaired in many genetic and pathological conditions associated to high CV risk such as dyslipidemia, chronic kidney disease, diabetes, inflammatory and autoimmune diseases, endocrine disorders, etc. The present review describes the current knowledge on HDL CEC modifications in these conditions, focusing on the most recent human studies and on genetic and pathophysiologic aspects. In addition, the most relevant strategies possibly modulating HDL CEC, including lifestyle modifications, as well as nutraceutical and pharmacological interventions, will be discussed. The objective of this review is to help understanding whether, from the current evidence, HDL CEC may be considered as a valid biomarker of CV risk and a potential pharmacological target for novel therapeutic approaches.

scholarly journals Fabry Cardiomyopathy: Current Practice and Future Directions

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1532
Author(s):  
Jeffrey Yim ◽  
Olivia Yau ◽  
Darwin F. Yeung ◽  
Teresa S. M. Tsang
Keyword(s):  
Fabry Disease ◽  
Early Stage ◽  
Point Of Care ◽  
Left Ventricular ◽  
The Body ◽  
Cardiac Biomarkers ◽  
Dried Blood Spot ◽  
Point Of Care Ultrasound ◽  
Enzyme Replacement ◽  
Blood Spot

Fabry disease (FD) is an X-linked lysosomal storage disorder caused by mutations in the galactosidase A (GLA) gene that result in deficient galactosidase A enzyme and subsequent accumulation of glycosphingolipids throughout the body. The result is a multi-system disorder characterized by cutaneous, corneal, cardiac, renal, and neurological manifestations. Increased left ventricular wall thickness represents the predominant cardiac manifestation of FD. As the disease progresses, patients may develop arrhythmias, advanced conduction abnormalities, and heart failure. Cardiac biomarkers, point-of-care dried blood spot testing, and advanced imaging modalities including echocardiography with strain imaging and magnetic resonance imaging (MRI) with T1 mapping now allow us to detect Fabry cardiomyopathy much more effectively than in the past. While enzyme replacement therapy (ERT) has been the mainstay of treatment, several promising therapies are now in development, making early diagnosis of FD even more crucial. Ongoing initiatives involving artificial intelligence (AI)-empowered interpretation of echocardiographic images, point-of-care dried blood spot testing in the echocardiography laboratory, and widespread dissemination of point-of-care ultrasound devices to community practices to promote screening may lead to more timely diagnosis of FD. Fabry disease should no longer be considered a rare, untreatable disease, but one that can be effectively identified and treated at an early stage before the development of irreversible end-organ damage.

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