Natural History Of Fabry Disease Research Articles

Fabry disease: integrative aspects from diagnosis to treatment

Aim: identify the main aspects of Fabry disease (FD) from clinical suspicion to diagnosis, its vascular and cellular effects, in addition to treatment. Methods: This study is an integrative review of the literature supported by the search for articles in databases, Pub Med, Lilacs, Scielo, journals, and websites, with the following descriptors “Fabry disease”, “Fabry Disease treatment”, “Agalsidase-β”, “Agalsidase-α”, “Migalatast”, “inflammatory biomarkers” and “oxidative stress”, using original research articles and reviews between the years 1991 and 2023. This bibliographic survey was carried out in the period 01/10/2022 to 20/04/2023. Results: From a total of 340 articles found, 85 articles were selected. Discussion: The natural history of FD appears to be very complex, with multisystemic involvement and phenotypic variability. The analysis of FD symptoms is essential to the early diagnosis, aiming for greater success in therapy and prognosis, ensuring better patients’ quality of life and survival. Conclusion: This review addresses the diagnosis and main therapeutic approaches to guide health professionals and researchers, and to stimulate the development of research on FD.

Fabry Disease practice resource: Focused revision

Fabry Disease practice resource: Focused revision

A 15-Year Perspective of the Fabry Outcome Survey

The Fabry Outcome Survey (FOS) is an international long-term observational registry sponsored by Shire for patients diagnosed with Fabry disease who are receiving or are candidates for therapy with agalsidase alfa (agala). Established in 2001, FOS provides long-term data on agala safety/efficacy and collects data on the natural history of Fabry disease, with the aim of improving clinical management. The FOS publications have helped establish prognostic and severity scores, defined the incidence of specific disease variants and implications for clinical management, described clinical manifestations in special populations, confirmed the high prevalence of cardiac morbidity, and demonstrated correlations between ocular changes and Fabry disease severity. These FOS data represent a rich resource with utility not only for description of natural history/therapeutic effects but also for exploratory hypothesis testing and generation of tools for diagnosis/management, with the potential to improve future patient outcomes.

Natural history of Fabry disease in male and female patients with the N215S genotype

Natural history of Fabry disease in male and female patients with the N215S genotype

X-chromosome inactivation in female patients with Fabry disease.

Fabry disease (FD) is an X-linked genetic disorder caused by the deficient activity of lysosomal α-galactosidase (α-Gal). While males are usually severely affected, clinical presentation in female patients may be more variable ranging from asymptomatic to, occasionally, as severely affected as male patients. The aim of this study was to evaluate the existence of skewed X-chromosome inactivation (XCI) in females with FD, its concordance between tissues, and its contribution to the phenotype. Fifty-six females with FD were enrolled. Clinical and biological work-up included two global scores [Mainz Severity Score Index (MSSI) and DS3], cardiac magnetic resonance imaging, measured glomerular filtration rate, and measurement of α-Gal activity. XCI was analyzed in four tissues using DNA methylation studies. Skewed XCI was found in 29% of the study population. A correlation was found in XCI patterns between blood and the other analyzed tissues although some punctual variability was detected. Significant differences in residual α-Gal levels, severity scores, progression of cardiomyopathy and deterioration of kidney function, depending on the direction and degree of skewing of XCI were evidenced. XCI significantly impacts the phenotype and natural history of FD in females.

Anderson-Fabry Disease: A Multiorgan Disease

Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by a deficiency of the enzyme α-galactosidase A. FD causes glycolipids, such as globotriaosylceramide (Gb3), to accumulate in the vascular endothelium of several organs (Fig. 2), including the skin, kidneys, nervous system, and heart, thereby triggering inflammation and fibrosis. These processes generally result in organ dysfunction, which is usually the first clinical evidence of FD. Patients with classic FD have various symptoms, eg, acroparesthesias, hypohidrosis, angiokeratomas, corneal opacities, cerebrovascular lesions, cardiac disorders, andrenal dysfunction.However, evolving knowledge about the natural course of disease suggests that it is more appropriate to describe FD as a disease with a wide spectrum of heterogeneously progressive clinical phenotypes. Indeed, most female heterozygotes develop symptoms due to yet undetermined mechanisms and a high percentage of females develops vital organ involvement including the kidneys, heart and/or brain about a decade later than males. Renal failure is a serious complication of this disease. Fabry nephropathy lesions are present and progress in childhood while the disease commonly remains silent by routine clinical measures. Early and timely diagnosis of Fabry nephropathy is crucial since late initiation of enzyme replacement therapy may not halt progressive renal dysfunction. This may be challenging due to difficulties in diagnosis of Fabry disease in children and absence of a sensitive non-invasive biomarker of early Fabry nephropathy. Accurate measurement of glomerular filtration rate and regular assessment for proteinuria and microalbuminuria are useful, though not sensitive enough to detect early lesions in the kidney. The principal clinical manifestations in Fabry disease consist of artery associated complications (such as cerebral disease and nephropathy), but the pathophysiology of this specific vasculopathy is unclear. Several studies indicate that the specific vascular lesions that are present in Fabry disease occur as a result of vascular dysfunction with major components being endothelial dysfunction, alterations in cerebral perfusion and a pro-thrombotic phenotype. Fabry cardiac involvement has several clinical manifestations (Table 10): concentric left ventricular hypertrophy without left ventricular dilation and severe loss of left ventricular systolic function, mitral and aortic valvulopathy, disorders of the atrioventricular conduction or repolarization, and compromised diastolic function. The neurological manifestations of Fabry disease include both peripheral nervous system and CNS involvement, with globotriaosylceramide accumulation found in Schwann cells and dorsal root ganglia together with deposits in CNS neurones. The main involvement of the CNS is attributable to cerebrovasculopathy, with an increased incidence of stroke. The abnormal neuronal accumulation of glycosphingolipid appears to have little clinical effect on the natural history of Fabry disease, with the possible exception of some reported mild cognitive abnormalities. The pathogenesis of Fabry vasculopathy remains poorly understood, but probably relates, in part, to abnormal functional control of the vessels, secondary to endothelial dysfunction as a consequence of α-galactosidase A deficiency. The diagnosis of Fabry disease is made in hemizygous males after the detection of the presence of angiokeratomas (Fig. 19 A, B), irregularities in sweating, edema, scant body hair, painful sensations, and of cardiovascular, intestinal, renal, ophthalmologic, phlebologic, and respiratory involvement. A deficiency of alpha-gal A in serum, leukocytes, tears, tissue specimens, or cultured skin fibroblasts further supports the diagnosis in male patients. Since heterozygous women show angiokeratomas in only about 30% of cases and may have alpha-gal A levels within normal range, genetic analysis is recommended. The resultant storage of undegraded glycolipids leads to the progressive development of potentially life-threatening manifestations affecting multiple organ systems in the body. The Mainz Severity Score Index (MSSI) (Table 12), a scoring system for patients with Fabry disease has been proven to be representative in patients with 'classic' Fabry disease and may be useful for monitoring clinical improvement in patients receiving enzyme replacement therapy. The MSSI of patients with AFD was significantly higher than that of patients with other severe debilitating diseases.

Fabry disease in children and response to enzyme replacement therapy: results from the Fabry Outcome Survey

The Fabry Outcome Survey (FOS) was established to extend the knowledge of the natural history of Fabry disease and to assess the effects of enzyme replacement therapy (ERT) with agalsidase alfa. As of March 2009, 64 boys and 34 girls with Fabry disease had enrolled in the FOS and been treated with agalsidase alfa for at least 6 months. The prevalence of symptoms tended to be reduced after 12 and 24 months of ERT in patients who experienced symptoms at baseline. In the entire population, non-significant decreases in the prevalence of gastrointestinal problems in boys and pain crises in girls were observed after 12-24 months. Kidney function and left ventricular mass indexed to height remained stable. Fifty-eight treatment-related adverse events were reported in 23 patients (21 boys and 2 girls), including 55 infusion reactions. Anti-agalsidase alfa IgG antibodies were found in two boys. No IgE antibodies were reported. This study represents the largest observational study of paediatric Fabry disease patients treated with ERT and indicates continued safety of long-term ERT in children. Continued long-term follow-up is recommended to determine early initiation of ERT, which could potentially slow or prevent the progression of serious morbidities of Fabry disease.

The natural history of fabry disease

Glycolipid accumulation leads to organ damage and renal, cardiac and cerebrovascular events in Fabry disease. Schiffmann et al1 conducted a chart review of 279 affected males and 168 females from 27 sites. The mean rate of glomerular filtration rate (eGFR) decline was –2.93 for males, and –1.02 ml/min/1.73 m2/year for females. Proteinuria, baseline eGFR 300 mg/24 h) was found in 43% and 26% of males and females with CKD stage 1, respectively, and the proportions were higher with more severe kidney involvement. Systemic blood pressure was ≥130/80 mm Hg in 48% and 67% of patients with eGFR ≥ and <60 ml/min/1.73 m2, respectively, with no significant differences between males and females. The most recent analysis3 shows that females who progress to ESRD do so at the same age as males, indicating that there is a subset of females with burden of disease as severe as male patients. Cardiac abnormalities are characterized mainly by left ventricular (LV) wall thickening without significant dilatation, and LV hypertrophy (LVH).4 In some patients the disease mimics a typical hypertrophic obstructive cardiomyopathy. Systolic function is largely preserved in a large majority of affected individuals. In contrast, mild to moderate impairment of diastolic filling is a relatively common finding. Electrocardiographic changes in Fabry disease are multiple and include atrioventricular conduction abnormalities, signs of LVH and repolarization abnormalities. Cardiac symptoms in patients with Fabry disease include shortness of breath on effort (related to LV diastolic dysfunction), vasospastic and/or exertional angina pectoris, and syncope. Linhart et al5 described the cardiac disease in Fabry patients. Gender, age, and glomerular filtration rate were independent determinants of LVH. Takenaka et al6 reviewed the so-called cardiac variant for patients with manifestations limited to the heart, and the terminal stage cardiac manifestations and autopsy findings for 7 patients with cardiac Fabry disease. Six patients died of heart failure and one of ventricular fibrillation. Echocardiograms and autopsy findings revealed LVH in all patients. Localized basal posterior wall thinning of the left ventricle was detected in the 6 patients who died of heart failure. All patients had severe left ventricular dysfunction. With a better understanding of the natural history of Fabry disease, intervention studies and treatment expectations can be better defined, with the goal of reducing loss of eGFR to an absolute minimum (<–1.0 ml/min/ 1.73 m2/year). Current treatment studies of advanced Fabry disease7 have been dominated by renal outcome events. If progression loss of eGFR can be controlled, then outcome studies can be focused on cardiovascular events.

Anderson-Fabry disease: developments in diagnosis and treatment

Anderson-Fabry disease (commonly known as Fabry disease) is an X-linked disorder that is caused by deficiency of the lysosomal enzyme a-galactosidase A. The resulting accumulation of globotriaosylceramide leads to a wide spectrum of clinical signs and symptoms that affect many organs, including the kidneys, heart and brain. In recent years, our understanding of the natural history of Fabry disease has improved considerably, as have methods of clinical characterization and diagnosis. It is now apparent that this disorder may be much more common than previously suspected. The long-term efficacy of enzyme replacement therapy (ERT) in reducing disease burden in patients with Fabry disease continues to be demonstrated in clinical trials and observational studies; however, it is clear that ERT has limitations. This review provides an overview of current issues in the diagnosis and treatment of patients with Fabry disease and considers what may lie ahead in this rapidly evolving therapeutic area.

Ear symptoms in children with Fabry disease: data from the Fabry Outcome Survey

Hearing loss and tinnitus are common symptoms in Fabry disease and increase in prevalence with age. This study aimed to provide an epidemiological description of hearing impairment and tinnitus in children with Fabry disease in the Fabry Outcome Survey (FOS), an international database to assess the natural history of Fabry disease and the efficacy of enzyme replacement therapy with agalsidase alpha. Signs and symptoms questionnaires were completed for 543 children with Fabry disease. Pure-tone audiograms were obtained from 101 children (53 girls, 48 boys). On questioning, 33% of the children (n = 179) reported subjective hearing impairment. However, when assessed by age-appropriate audiometry, only 19 of 101 patients (19%) had a persistent hearing loss at least one frequency. Of these, 14 had a high-frequency hearing loss, 4 a pan-frequency hearing loss, and 1 a pattern typical of noise-induced loss. Of the 101 children with audiometry, 44 complained of tinnitus. Only 2 children reported sudden hearing loss, which was not verified by audiometry. Children with tinnitus had greater disease severity scores. Hearing loss is a well-known clinical manifestation in patients with Fabry disease. It was reported in significant numbers of children in the FOS signs and symptoms questionnaire, but confirmed in only 19% by formal audiometry. The subjective hearing impairment may have been due to middle-ear effusions in many cases. Tinnitus is a well-recognized symptom in Fabry disease and can present in childhood. The presence of tinnitus correlated with overall disease severity.

Natural course of Fabry disease: changing pattern of causes of death in FOS – Fabry Outcome Survey

Background:Fabry disease is a rare X-linked lysosomal storage disorder characterised by severe multisystemic involvement that leads to major organ failure and premature death in affected men and women. Over the...

106. Natural history of Fabry disease: Progression of the nephropathy in a large series of affected males and heterozygous females

106. Natural history of Fabry disease: Progression of the nephropathy in a large series of affected males and heterozygous females

The cerebral vasculopathy of Fabry disease

Fabry disease is an X-linked disorder affecting both males and females. It is associated with an increased risk of stroke in up to 4% of patients below 55 years of age in the general population. The cerebral vasculopathy consists of ischemic strokes involving large and small vessels. The neuronal accumulation of glycosphingolipids appears to have no clinical effect on the natural history of Fabry disease with the possible exception of some reported mild cognitive abnormalities. The pathogenesis of Fabry vasculopathy remains poorly understood but is associated with abnormal functional control of the vessel secondary to endothelial dysfunction, cerebral hyper-perfusion and a prothrombotic state with likely increased production of reactive oxygen species. These abnormalities are further modified by genetic and possibly other vascular risk factors. This vasculopathy illustrates the role of glycolipids in this and possibly other types of cerebral vasculopathies. Therapy is preventive relying on standard medical care and in particular on anti-platelet agents such as clopidogrel.

Clinical manifestations of Fabry disease in children: Data from the Fabry Outcome Survey

Fabry disease is a rare X-linked disorder caused by deficient activity of the enzyme alpha-galactosidase A. This produces progressive lysosomal accumulation of globotriaosylceramide throughout the body, leading to organ failure and premature death. Here, we present the clinical manifestations of Fabry disease in children enrolled in FOS--the Fabry Outcome Survey--a European database of the natural history of Fabry disease and the effects of enzyme replacement therapy with agalsidase alfa (Replagal). Currently, there are 545 patients in FOS, from 11 European countries. We analysed the baseline demographic and clinical characteristics of 82 of these patients (40 boys, 42 girls) who were below 18 y of age. The median age at evaluation (defined as the median age at entry into FOS) was 12.5 and 13.2 y for boys and girls, respectively. The most frequent early clinical manifestations of Fabry disease were neurological (acroparaesthesiae, altered temperature sensitivity) and gastrointestinal symptoms (altered bowel habits and abdominal pain), which were documented in about 80% and 60% of patients, respectively, at the time of evaluation and subsequent entry into FOS. Tinnitus, vertigo, fatigue and angiokeratoma were present in over 40% of patients. Symptoms were noted in early childhood and occurred with similar frequency in boys and girls, although the onset of symptoms was 2-5 y later in girls than in boys. There was an approximately 3-y delay from onset of symptoms to diagnosis, and patients were frequently misdiagnosed. Although the life-threatening complications of Fabry disease, such as stroke and renal and heart failure, are not seen in children, the present analysis shows that other symptoms are common and may have an impact on quality of life.

Clinical manifestations of Fabry disease in children: Data from the Fabry Outcome Survey

Abstract Background: Fabry disease is a rare X‐linked disorder caused by deficient activity of the enzyme α‐galactosidase A. This produces progressive lysosomal accumulation of globotriaosylceramide throughout the body, leading to organ failure and premature death. Aim: Here, we present the clinical manifestations of Fabry disease in children enrolled in FOS—the Fabry Outcome Survey—a European database of the natural history of Fabry disease and the effects of enzyme replacement therapy with agalsidase alfa (Replagal™). Methods: Currently, there are 545 patients in FOS, from 11 European countries. We analysed the baseline demographic and clinical characteristics of 82 of these patients (40 boys, 42 girls) who were below 18 y of age. The median age at evaluation (defined as the median age at entry into FOS) was 12.5 and 13.2 y for boys and girls, respectively. Results: The most frequent early clinical manifestations of Fabry disease were neurological (acroparaesthesiae, altered temperature sensitivity) and gastrointestinal symptoms (altered bowel habits and abdominal pain), which were documented in about 80% and 60% of patients, respectively, at the time of evaluation and subsequent entry into FOS. Tinnitus, vertigo, fatigue and angiokeratoma were present in over 40% of patients. Symptoms were noted in early childhood and occurred with similar frequency in boys and girls, although the onset of symptoms was 2–5 y later in girls than in boys. There was an approximately 3‐y delay from onset of symptoms to diagnosis, and patients were frequently misdiagnosed. Conclusion: Although the life‐threatening complications of Fabry disease, such as stroke and renal and heart failure, are not seen in children, the present analysis shows that other symptoms are common and may have an impact on quality of life.

Natural history of Fabry disease in females in the Fabry Outcome Survey

Background: Fabry disease is a rare X linked lysosomal storage disorder resulting from deficiency of α-galactosidase A activity. Although the severity of clinical features in male patients is well described,...

Natural history of Fabry disease in males: preliminary observations.

A large cohort of patients with Fabry disease is being studied to determine the natural history of the disease and how this relates to the specific mutation involved and the amount of residual alpha-galactosidase A activity. To date, we have investigated the progression of cerebral lesions and stroke, as identified by magnetic resonance imaging, and renal disease. Results have shown that cerebral lesions do not appear until 23 years of age, but are present in all patients by 55 years of age. The peak onset of proteinuria occurred in the fourth decade, and the peak onset of chronic renal insufficiency and end-stage renal disease occurred in the fifth decade of life. Renal outcome was related to the type of mutation and residual enzyme activity. Data from these studies in untreated patients will be important when assessing the long-term efficacy of enzyme replacement therapy.

Natural history of Fabry disease in affected males and obligate carrier females.

Natural history of Fabry disease in affected males and obligate carrier females.