Symptoms Of Fabry Disease Research Articles

Fabry disease: multidisciplinary evaluation after 10 years of treatment with agalsidase Beta.

Fabry disease is an X linked disorder of metabolism due to deficient α-galactosidase A activity. Enzyme replacement therapy (ERT) with agalsidase Beta was approved by EMA in 2001 and FDA in 2003. Six patients were enrolled. Baseline data was measured for renal, cardiac, and cerebrovascular functioning. We compared baseline quality of life scales with the current results. These parameters were assessed during the 10years of follow-up period. Before ERT four patients showed normal eGFR, one stage 2 of CKD, and one hyperfiltration stage. All presented microalbuminuria and just two cases showed proteinuria. After 10years of ERT, no patient showed decrease in renal functioning. One patient decreased from proteinuria to microalbuminuria range. Before treatment one case showed left ventricular (LV) hypertrophy and LV Mass Index was abnormal in two female patients. After 10years echocardiographic values did not present progression to LVH and one female showed regression to normal values of LV posterior wall and interventricular septum. Brain MRI showed ischemic lesions in one female and vertebrobasilar dolichoectasia in one male. From baseline and during the follow-up period MRI did not progress to new ischemic lesions and there were no clinical signs of cerebrovascular damage. After 10years quality of life showed improvement in all domains measured. Early treatment of agalsidase Beta is related to a better outcome regarding stability and regression of signs and symptoms in Fabry disease. Our results in patients with mild organ involvement showed good outcomes and support an early and continuous ERT.

A Retrospective Survey Studying the Impact of Fabry Disease on Pregnancy.

Fabry disease (FD) is a lysosomal storage disorder resulting from a deficiency of lysosomal enzyme α-galactosidase A (α-gal A). Reduced or missing α-gal A enzyme results in the storage of globotriaosylceramide (GL3) and related glycosphingolipids in the cellular lysosomes throughout the body. The majority of GL3 buildup occurs in the body's vasculature resulting in narrowed blood vessels and an increased risk for strokes, transient ischemic attacks, and deep vein thrombosis. Theoretical concerns have been raised about increased pregnancy complications in women affected by FD as glycosphingolipid storage has been found in both maternal- and fetal-derived placental tissues. This retrospective study was conducted to better understand risks for women with FD during pregnancy. Survey questions included queries about prenatal medications, teratogenic exposures, prenatal testing, common pregnancy complications, Fabry symptoms during pregnancy, obstetrical history, and immediate neonatal history. In total, 41 affected women completed the survey. Results indicate several Fabry-related symptoms and features may worsen during pregnancy, including gastrointestinal symptoms, acroparesthesias, proteinuria, headaches, and postpartum depression. Although no life-threatening complications were reported, a statistically significant increased frequency of hypertension was observed when comparing data from this study to the general population (p < 0.05) and previous publications (p < 0.001). Limitations include sample size and recall bias. Though this survey sampling of women was small and required women to recall their past pregnancy experiences, the findings suggest that when pregnant, women with FD should be aware of potential worsening of FD symptoms and may benefit from consulting with a maternal-fetal medicine specialist.

Fabry disease: is there a role for enzyme replacement therapy?

Fabry disease: is there a role for enzyme replacement therapy?

What lies beneath: Fabry nephropathy in a female patient with severe cerebrovascular disease

Fabry disease is an X-linked inborn error of metabolism, which is caused by the deficiency of &#945;-galactosidase A, leading to progressive accumulation of neutral glycosphingolipids and a-galactosyl breakdown products in most body fluids and several tissues, resulting in the clinical manifestations. The onset of Fabry disease symptoms in females is not observed as early as in males. We report a novel presentation of Fabry disease in a female patient with medical history of relapsing strokes and brain magnetic resonance angiography showing signs of microangiopathy and multiple lacunar strokes that were first diagnosed as Moyamoya disease (a chronic progressive cerebrovascular disease). The patient subsequently displayed increased levels of serum creatinine and proteinuria. Diagnosis of Fabry disease was made by a renal biopsy and was confirmed by molecular studies showing a missense mutation: c1066C > T (het) [R356W]. The diagnosis was delayed by 21 years with respect to her first symptom (stroke), probably because her initial clinical presentation was neurological and diagnosed as Moyamoya disease. Other factors that contributed to the delay of the diagnosis were the lack of acute or chronic pain (neuropathic pain) and angiokeratomas. Some similarities in the pathogenic aspects of the patient's vascular lesions lead us to speculate that this patient has Fabry disease, with a phenotype that had not yet been described. It is necessary to be aware of this possibility to avoid misdiagnosis of Fabry disease as Moyamoya disease.

Fabry patients' experiences with the timing of diagnosis relevant for the discussion on newborn screening

This study aimed to explore Fabry disease (FD) patients' experiences with the timing of their diagnosis and identify important patient-oriented themes relevant to discussions about the need for newborn screening (NBS) for this disorder.Thirty FD patients (13 males) were included in a qualitative study involving semi-structured interviews. The interviews were audiorecorded and transcribed, and the transcripts were analyzed to identify themes that captured the patients' experiences.The interview analysis revealed six relevant themes. One of these was the impact of a delayed diagnosis on severely affected patients, who often felt misunderstood and were frequently misdiagnosed. In contrast, some patients mentioned the drawbacks of presymptomatic diagnosis, which was associated with labeling and medicalization. In addition, the ability to anticipate future FD-related problems was considered both an advantage and a disadvantage of early diagnosis. Still, patients reported that they felt that an early FD diagnosis could prevent disease progression through the timely initiation of treatment.This study identified several relevant themes that reflect both the phenotypic heterogeneity of the disease and the substantial differences between patients' experiences with and without FD symptoms before diagnosis and among the patients in each group. These results add considerable nuances to the discussion about NBS programs for FD and should be incorporated into the debate.

Fabry Disease

Fabry disease (FD) is an X-linked lysosomal storage disorder caused by accumulation of Gb-3 (globotriaosylceramide) in cellular lysosomes of tissues throughout the body. With advancing age, lysosomal Gb-3 accumulates in blood vessel walls, nerve cells, smooth muscle, and vital organs. Premature death commonly results from renal failure, heart attack, and stroke when the diagnosis is delayed or overlooked. One of the earliest and most distinctive physical features of FD is a whorl-like keratopathy. This finding is easily identifiable during a routine eye examination with a slit lamp, making eye care practitioners uniquely postured to identify patients and families with this incurable genetic disorder. Much of the pain, suffering, and adverse impact of FD can be avoided if an alert eye care expert sees the patient at an early age, identifies the condition, and makes the appropriate referral. The importance of obtaining a thorough medical history, ancestral health history, and review of systems to correlate ocular and systemic manifestations is emphasized. This report reviews the multisystem involvement of FD and describes the clinical characteristics and expected chronological appearance of ophthalmic and systemic manifestations. The discoveries of late-onset variants, increased prevalence, and modified inheritance pattern of FD are discussed. The profound therapeutic effects of recombinant enzyme replacement therapy (ERT) on multiple organ systems are detailed and demonstrated in a Fabry proband. Improved quality and quantity of life after initiation of ERT underscore the importance of early recognition and correlation of FD symptoms and clinical signs. Treatment strategies and the effectiveness of new adjunctive chaperone therapy are addressed.

Phenotypical characterization of α-galactosidase A gene mutations identified in a large Fabry disease screening program in stroke in the young

ObjectiveIn the Belgian Fabry Study (BeFaS), the prevalence of Fabry disease was assessed in 1000 young patients presenting with stroke, unexplained white matter lesions or vertebrobasilar dolichoectasia. The results of the BeFaS suggested that Fabry disease may play a role in up to 1% of young patients presenting with cerebrovascular disease. However, the clinical relevance was unclear in all cases. We report on detailed phenotyping in subjects identified with α-galactosidase A (α-Gal A) enzyme deficiency or GLA mutations identified in the BeFaS (n=10), and on the results of family screening in this population. MethodsFamily screening was performed to identify additional mutation carriers. Biochemical and/or clinical evaluation of all subjects (BeFaS index patients and relatives carrying a GLA mutation) was performed. ResultsGenetic family screening revealed 18 additional GLA mutation carriers. Bloodspot α-Gal A enzyme activity was normal in all GLA mutation carriers, even in 2 males with the p.A143T mutation. Plasma Gb3 and lyso-Gb3 levels were normal in all subjects. Elevated Gb3 in urine was detected in 2 subjects. Some classic clinical signs of Fabry disease, like angiokeratoma or cornea verticillata, could not be detected in our population. Cardiac symptoms of Fabry disease were found in 6 out of 10 p.A143T carriers. No signs of cerebrovascular disease were found in the relatives with a GLA mutation. ConclusionsWe could not identify mutations causing the classical clinical phenotype of Fabry disease in our cerebrovascular disease population. Enzyme activity analysis in bloodspots and plasma may fail to identify late-onset variants of Fabry disease. We recommend genetic testing when an atypical, late-onset variant of Fabry disease is suspected in a male cerebrovascular disease patient. However, this may lead to the identification of non-disease causing or controversial genetic variants.

Is it or is it not a pathogenic mutation? Is it or is it not the podocyte?

Is it or is it not a pathogenic mutation? Is it or is it not the podocyte?

Fabry disease: raising awareness of the disease among physicians

Fabry disease is an X-linked inherited lysosomal disorder due to dysfunctions of the lysosomal enzyme alpha-galactosidase A, causing insufficient breakdown of glycolipids, which are stored in the eyes, kidneys, autonomic nervous system, skin, vessels and cardiovascular system. Manifestations of Fabry disease include progressive renal and cardiac insufficiency, neuropathic pain, stroke and cerebral disease, skin and gastrointestinal symptoms. Clinical onset usually occurs in childhood, but many severe patients are diagnosed in adulthood. Females may be severely affected as males and both may die prematurely due to stroke, heart disease and renal failure. Enzyme replacement therapy can stabilize or reduce the progression of the disease. There is a need to improve the knowledge of Fabry disease, as an early therapy may prevent complications of the disease. This brief overview aims to raise awareness of the signs and symptoms of Fabry disease and to summarize the effects of treatments.

Broad spectrum of Fabry disease manifestation in an extended Spanish family with a new deletion in the GLA gene.

BackgroundFabry disease (FD) is an X-linked inherited disease based on the absence or reduction of lysosomal-galactosidase (Gla) activity. The enzymatic defect results in progressive impairment of cerebrovascular, renal and cardiac function. Normally, female heterozygote mutation carriers are less strongly affected than male hemizygotes aggravating disease diagnosis.MethodClose examination of the patients by renal biopsy, echo- and electrocardiography and MRI. Blood work and subsequent DNA analysis were carried out utilizing approved protocols for PCR and Sequencing. MLPA analysis was done to unveil deletions within the GLA gene locus. Quantitative detection of Glycolipids in patient plasma and urine were carried out using HPLC/MS-MS and ESI-MS.ResultsIn the presented case, a female index patient led to the examination of three generations of a Spanish family. She presented with severe oto-cochlear symptoms and covert renal and cardiac involvement. While conventional sequencing failed to detect a causative mutation, MLPA analysis revealed a deletion within the GLA gene locus, which we were able to map to a region spanning exon 2 and adjacent intronic parts. The analysis of different biomarkers revealed elevated lyso-Gb3 levels in all affected family members.ConclusionOur findings highlight the broad intrafamilial spectrum of symptoms of FD and emphasise the need to use MLPA screening in symptomatic females without conclusive sequencing result. Finally, plasma lyso-Gb3 proved to be a reliable biomarker for the diagnosis of FD.

Possible role of transforming growth factor-β1 and vascular endothelial growth factor in Fabry disease nephropathy

Fabry disease is a lysosomal storage disorder (LSD) caused by deficiency of α-galactosidase A (α-gal A), resulting in deposition of globotriaosylceramide (Gb3; also known as ceramide trihexoside) in the vascular endothelium of many organs. A gradual accumulation of Gb3 leads to cardiovascular, cerebrovascular and renal dysfunction. Endothelial cell dysfunction leads to renal complications, one of the main symptoms of Fabry disease. However, the pathological mechanisms by which endothelial dysfunction occurs in Fabry disease are poorly characterized. The purpose of this study was to investigate whether the expression of transforming growth factor-β1 (TGF-β1) and vascular endothelial growth factor (VEGF) is associated with the renal pathogenesis of Fabry disease. We found that the protein expression levels of renal thrombospondin-1 (TSP-1), TGF-β1 and VEGF were higher in the kidneys from Fabry mice compared to wild-type mice. The expression levels of VEGF receptor 2 (VEGFR2), fibroblast growth factor-2 (FGF-2) and phospho-p38 (P-p38) were also higher in the kidneys from Fabry mice compared with wild-type mice. Activities of cysteine aspartic acid protease (caspase)-6 and caspase-9 were higher in kidneys from Fabry than from the wild-type mice. These results suggest that overexpression of TGF-β1 and VEGF in the Fabry mouse kidney might contribute to Fabry disease nephropathy by inducing apoptosis. To test whether Gb3 accumulation can induce apoptosis, we incubated bovine aortic endothelial cells with Gb3 and found increased expression of TGF-β1, VEGFR2, VEGF, FGF-2 and P-p38. The combination of increased expression of TGF-β1 and VEGF caused by Gb3 accumulation may allow upregulation of FGF-2, VEGFR2 and P-p38 expression, and these changes may be associated with Fabry disease nephropathy by inducing apoptosis.

P23—New Guidelines for the Evaluation and Management of Fabry Disease in Children

AND MANAGEMENT OF FABRY DISEASE IN CHILDREN A. Tylki-Szymanska; R.J. Hopkin; M. Banikazemi; D.P. Germain; M. Mauer; D.G. Warnock; and W.A. Wilcox Children’s Memorial Health Institute, Warsaw, Poland; Cincinnati Children’s Hospital, Cincinnati, Ohio; Columbia University College of Physicians and Surgeons, New York, New York; University of Versailles, Hopital Raymond Poincare, Garches, France; University of Minnesota, Minneapolis, Minnesota; University of Alabama at Birmingham, Birmingham, Alabama; and Medical Genetics Institute, Cedars-Sinai Medical Center, and Department of Pediatrics, UCLA School of Medicine, Los Angeles, California Introduction: Fabry disease (FD) is an X-linked lysosomal storage disorder, characterized by decreased or absent activity of lysosomal -galactosidase A. As a result of this enzyme deficiency, globotriaosylceramide (GL-3) and other glycosphingolipids accumulate within various tissues and eventually impair vital organ function, putting patients with FD at risk for developing renal failure, cardiovascular dysfunction, and stroke. The initial signs and symptoms of FD, including neuropathic pain in the extremities, hypohidrosis, angiokeratomas, and gastrointestinal discomfort, generally appear during childhood. More serious complications of FD can also occur during childhood, including proteinuria, valvular dysfunction, conduction abnormalities, left ventricular hypertrophy and arrhythmia. Aim & Methods: In view of the growing recognition that significant manifestations of FD can occur during childhood, an international group of physicians who have pediatric patients enrolled in the Fabry Registry developed a set of specific guidelines for assessing FD in children based on evidence from the Fabry Registry and published literature. Results: The general types of assessments recommended for children with FD include: medical/family history (gastrointestinal, pain, sweating; heat/cold intolerance); physical examination (vital signs, height, weight, blood pressure); patient-reported outcomes (quality of life, fatigue, pain); laboratory testing (measured glomerular filtration rate, albuminuria/proteinuria); diagnostic testing (enzyme activity, genotype); specialized laboratory testing (antibodies, plasma GL-3); ophthalmology (slit-lamp examination); other studies (audiologic evaluation, cranial magnetic resonance imaging [T1, T2, FLAIR], echocardiography and ECG); and treatment/medication history (enzyme-replacement therapy status, concurrent medications). Conclusions: This new Pediatric Minimum Recommended Schedule of Assessments will increase the medical community’s awareness of the burden of FD in children, assist with monitoring, and improve the outcome for these young patients.

P03—Excessive Daytime Sleepiness is a Common Symptom in Fabry Disease

Fabry disease (FD) is an X-linked lysosomal storage disorder characterized by a deficient activity of the enzyme α-galactosidase A, resulting in a vasculopathic involvement of various organ systems, e.g. cerebral structures. Marked cerebral vasculopathy with subsequent white matter lesions (WML) are a frequent finding in FD patients. Recent studies discussed an association between cerebral white matter changes and sleeprelated disturbances of breathing, which may lead to excessive daytime sleepiness (EDS). A 56-year-old Caucasian female FD patient with EDS was admitted to our sleep laboratory. Overnight polysomnography showed a Cheyne-Stokes respiration pattern with significant O2 desaturation. MR imaging revealed confluent WML including the brain stem, but no renal or cardiac involvement. We then evaluated the clinical data of 49 genetically proven FD patients (27 males; mean age 43 years) from our FD centre. With a frequency of 68%, EDS exceeds the prevalence of other common symptoms of FD (angiokeratomas 61%; acroparaesthesia 51%; renal involvement 29%; cardiac involvement 27%), and the prevalence of chronic fatigue (48%). EDS was independently associated with the physical component summary of the SF-36 data (corrected R 2 = –0.323, p < 0.001). EDS and age explained a quarter of variance in mental component summary (corrected R 2 = –0.253, p < 0.001). We conclude that EDS is a common and underdiagnosed symptom in FD patients, accompanied by a significant impact on quality of life. EDS might be caused by central breathing disorders due to an affection of brain regions associated with respiratory control in FD.

Endocrinology

Despite the generally increased awareness of signs and symptoms of Fabry disease, due to the possibility of enzyme-replacement treatment (ERT), only a few reports have been published on endocrine dysfunction in this patient group.

Neuropathic Pain

Neuropathic pain is very often the earliest symptom of Fabry disease. Episodes of severe burning pain may occur from early childhood, typically in the feet and hands. These episodes are usually triggered by febrile infections, heat or cold exposure, physical exertion, or emotional stress and are known as “Fabry crises.” Often, the pain experienced by these children is misinterpreted as a symptom of infection rather than being recognized as a manifestation of Fabry disease. About 75% of adults with Fabry disease experience pain.

リハビリテーションにてめまいの改善をみとめたFabry病の1症例

Fabry disease is an X-linked recessive disorder involving progressive lysosomal deposition of globotriaosylceramide (GL-3) in cells caused by a deficient activity of the enzyme α-galactosidase A (α-Gal A). Hearing loss, tinnitus, and dizziness are common symptoms in Fabry disease. We present herein on a case of Fabry disease in a 56-year-old man with bilateral hearing loss, tinnitus, and dizziness during walking. Rehabilitation therapy for adaptation of the vestibulo-ocular system was performed for dizziness during walking. The patient was examined by questioning, use of the visual analogue scale (VAS), and computerized dynamic posturography (Equitest). After 4 months of rehabilitation, VAS score and Equitest results improved. Rehabilitation therapy for adaptation of the vestibulo-ocular system may be effective for Fabry disease dizziness.

Diagnostic dilemma: A young woman with Fabry disease symptoms, no family history, and a “sequencing cryptic” α-galactosidase a large deletion

Fabry disease, an X-linked lysosomal storage disorder, results from the deficient activity of α-galactosidase A (α-Gal A). In affected males, the clinical diagnosis is confirmed by the markedly decreased α-Gal A activity. However, in female heterozygotes, the α-Gal A activity can range from low to normal due to random X-chromosomal inactivation, and diagnostic confirmation requires identification of the family's α-Gal A gene mutation. In a young female who had occasional acroparesthesias, corneal opacities, and 15 to 50% of the lower limit of normal leukocyte α-Gal A activity, α-Gal A sequencing in two expert laboratories did not identify a confirmatory mutation, presenting a diagnostic dilemma. A renal biopsy proved diagnostic and renewed efforts to detect an α-Gal A mutation. Subsequent gene dosage analyses identified a large α-Gal A deletion confirming her heterozygosity, and she was started on enzyme replacement therapy. Thus, gene dosage analyses can detect large deletions (>50bp) in suspect heterozygotes for X-linked and autosomal dominant diseases that are “sequencing cryptic,” resolving molecular diagnostic dilemmas.

Brain MRI findings in patients with Fabry disease

Background To evaluate the presence of ischemic and hemorraghic lesions in brain MRI of patients with Fabry disease (FD). Methods Brain MRI studies in 46 consecutive patients were evaluated using classic sequences as well as GRE-weighted images, for ischemic lesions and chronic microbleed detection. Of the 36 adult patients (15 males, mean age 31.2 years; 21 females, mean age 41.6 years). All had signs or symptoms of FD but lacked history of stroke or TIA. Results Ten patients under 20 years of age initially presented a normal MRI. One child developed a hyperintense occipital lesion on T2-weighted imaging during control MRI. Sixteen adult patients (44.4%) had brain MRI evidence of small vessel disease in the basal ganglia, corona radiata, thalamus or brainstem, as well as in the periventricular white matter. Patients with MRI abnormalities were older (45.6 vs 30.9 years, p = 0.005), with more vascular risk factors (1.2 vs 0.6 p = 0.043). Three women (mean age 59.5 years) presented deep chronic microbleeds identified by GRE. Moreover, Flair and T2-weighted images revealed white matter disease and deep gray matter involvement. Conclusion 44.4% of adult patients with FD without clinical history of CVA or prior dialysis had evidence of small vessel disease on MRI and 11% showed cerebral microbleeds. FD is a treatable disorder that should be routinely included in the differential diagnosis of ischemic and microhemorraghic lesions in young adults.

Response of women with Fabry disease to enzyme replacement therapy: Comparison with men, using data from FOS—the Fabry Outcome Survey

Fabry disease (α-galactosidase A deficiency) is an X-linked disorder. Women who are heterozygous for disease-causing mutations often manifest signs and symptoms of Fabry disease, but most studies of the effects of enzyme replacement therapy (ERT) have included only men. To date, no direct comparison has been made of the relative effectiveness of long-term ERT between men and women. The aim of this analysis was to report the effectiveness of agalsidase alfa in a cohort of 78 women treated for 4 years and to compare outcomes with those of 172 men. All data were obtained from the Fabry Outcome Survey—an international database of patients with Fabry disease sponsored by Shire Human Genetic Therapies. Quantifiable clinical parameters were assessed at baseline and the 4-year time point. Measures of pain, health-related quality of life, cardiac structure and function, and renal function changed to a similar extent in women and men during treatment, with the exception of left ventricular mass, which only reduced significantly in women. Changes in the presence of each of 27 clinical features after 4 years of ERT were evaluated in two subpopulations: patients with and patients without clinical features at baseline. It was clear for most types of clinical features that a number of women with a feature at baseline were no longer reported to have it at the 4-year time point, and that clinical features were observed in only a small percentage of women in whom they had been absent at baseline. The percentage of patients who were symptomatic at the 4-year time point was calculated for each type of clinical feature. The results showed no significant differences between men and women for most clinical features evaluated. Overall, both sexes responded to agalsidase alfa in a similar way, suggesting there should be no difference in the criteria for assessment of treatment in women and men.

A Concise Synthesis of Globotriaosylsphingosine

AbstractGlobotriaosylsphingosine (lysoCTH) is produced in the cell by deacylation of the globo‐sphingolipid globotriaosylceramide. The latter compound is the major storage material encountered in Fabry patients, an inherited lysosomal storage disorder characterized by partially impaired α‐galactosidase A (GLA) activity. Recent findings suggest that lysoCTH, next to its acylated precursor, is an important causative of Fabry disease symptoms. The glycolipid is thus a relevant synthetic target, and we here report on its efficient synthesis. Key to our strategy is the use of 4,6‐O‐di‐tert‐butylsilylene‐protected D‐galactose donors to yield D‐Gal‐α‐D‐Gal linkages with high stereoselectivity. In our optimized route we make use of acyl protecting groups to mask most of the hydroxy functions in the carbohydrate building blocks to facilitate straightforward global deprotection.