Fabry disease in genetic counseling practice: recommendations of the National Society of Genetic Counselors (original) (raw)
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Natural history of Fabry disease in females in the Fabry Outcome Survey
Journal of Medical Genetics, 2005
Background: Fabry disease is a rare X linked lysosomal storage disorder resulting from deficiency of agalactosidase A activity. Although the severity of clinical features in male patients is well described, only recently have studies reported the high prevalence of disabling clinical features in heterozygous females. Aims: This study sets out to examine the clinical features and natural history of Fabry disease in further detail in a large group of female patients. Methods: Data were obtained from 303 females enrolled in the Fabry Outcome Survey. Pain was assessed using the Brief Pain Inventory, and health related quality of life (HRQoL) was assessed using the European Quality of Life Questionnaire. A modified version of the Mainz Severity Score Index was also applied. Data on left ventricular mass (LVM) index, mean ventricular wall thickness, and glomerular filtration rate (GFR) were used to assess cardiac and renal involvement. Results: The most commonly reported clinical features in females were neurological (77%) and cardiac (59%). A history of renal involvement was recorded in 40% of cases. Neurological features were the earliest to develop (mean age: 16 years), whereas cardiac (mean age: 33.5 years) and renal (mean age: 37.3 years) features developed later. LVM index increased exponentially with age. In addition, age was negatively correlated with estimated GFR and HRQoL. Conclusions: Females with Fabry disease report important age related clinical features and clinical investigation demonstrates evidence of disease progression. This study highlights the importance of careful and longitudinal assessment of female heterozygote patients with Fabry disease.
Journal of Inherited Metabolic Disease, 2007
The Fabry Registry is a global observational research platform established to define outcome data on the natural and treated course of this rare disorder. Participating physicians submit structured longitudinal data to a central-Communicating editor: Verena Peters Competing interests: Authors may have provided paid and unpaid consultancy services for Genzyme, may have been in receipt of travel expenses to attend meetings and may have participated in a number of clinical trials sponsored by Genzyme. This work was supported by grants from Genzyme Corporation, which also maintains the central Fabry Registry database, but the authors do not have financial interests related to it. All support to physicians participating in the Fabry Registry is conducted under strict guidelines for disclosure and compliance. References to electronic databases: Fabry disease (OMIM 301500); α-galactosidase A (α-Gal A; EC 3.2.1.22
Genotype and phenotype in Fabry disease: analysis of the Fabry Outcome Survey
Acta Paediatrica, 2007
Aim: Mutations of the gene (GLA) encoding a-galactosidase A are implicated in Fabry disease, a progressive, X-chromosomal inherited lysosomal storage disorder. FOS-the Fabry Outcome Survey-was established as a long-term surveillance study to describe the natural course of Fabry disease and its response to enzyme replacement therapy in a large cohort of European patients. Clinical phenotype, age of onset and course of Fabry disease are very variable, even within the same family, which makes it difficult to define a genotype-phenotype relationship by analysing individual patients. The FOS database contains detailed medical information on a large cohort of patients and thus has the potential to provide important information to address this question. Methods: At the time of analysis, information on 545 patients belonging to 157 families from nine European countries had been entered into the FOS database. A GLA mutation has been reported in 365 individuals (65% and 68% of all males and females, respectively) in FOS. These data were used to analyse the relationship between genotype and phenotype in Fabry disease. Results: A highly significant positive correlation was found between the age at entry into FOS and the FOS Severity Index in male patients with GLA missense mutations (p50.001) as well as in those carrying other types of mutations (p50.001). A positive correlation was also found between the age at entry into FOS and the number of affected organs in male patients with missense mutations, irrespective of whether the change in the amino acid side chain predicted in the a-galactosidase A protein was classified as a conservative or non-conservative change. Conclusion: The data presented here suggest that there is a correlation between genotype and clinical severity.
Orphanet Journal of Rare Diseases, 2022
This consensus statement by a panel of Fabry experts aimed to identify areas of consensus on conceptual, clinical and therapeutic aspects of Fabry disease (FD) and to provide guidance to healthcare providers on best practice in the management of pediatric and adult patients with FD. This consensus statement indicated the clinical heterogeneity of FD as well as a large number of pathogenic variants in the GLA gene, emphasizing a need for an individualized approach to patient care. The experts reached consensus on the critical role of a high index of suspicion in symptomatic patients and screening of certain at-risk groups to reveal timely and accurate diagnosis of FD along with an increased awareness of the treating physician about the different kinds of pathogenic variants and their clinical implications. The experts emphasized the crucial role of timely recognition of FD with minimal delay from symptom onset to definite diagnosis in better management of FD patients, given the likel...
Acta Paediat, 2007
Aim: Mutations of the gene (GLA) encoding a-galactosidase A are implicated in Fabry disease, a progressive, X-chromosomal inherited lysosomal storage disorder. FOS-the Fabry Outcome Survey-was established as a long-term surveillance study to describe the natural course of Fabry disease and its response to enzyme replacement therapy in a large cohort of European patients. Clinical phenotype, age of onset and course of Fabry disease are very variable, even within the same family, which makes it difficult to define a genotype-phenotype relationship by analysing individual patients. The FOS database contains detailed medical information on a large cohort of patients and thus has the potential to provide important information to address this question. Methods: At the time of analysis, information on 545 patients belonging to 157 families from nine European countries had been entered into the FOS database. A GLA mutation has been reported in 365 individuals (65% and 68% of all males and females, respectively) in FOS. These data were used to analyse the relationship between genotype and phenotype in Fabry disease. Results: A highly significant positive correlation was found between the age at entry into FOS and the FOS Severity Index in male patients with GLA missense mutations (p50.001) as well as in those carrying other types of mutations (p50.001). A positive correlation was also found between the age at entry into FOS and the number of affected organs in male patients with missense mutations, irrespective of whether the change in the amino acid side chain predicted in the a-galactosidase A protein was classified as a conservative or non-conservative change. Conclusion: The data presented here suggest that there is a correlation between genotype and clinical severity.
The early clinical phenotype of Fabry disease: a study on 35 European children and adolescents
European Journal of Pediatrics, 2003
Fabry disease (FD) is a debilitating progressive multisystem X-linked lysosomal storage disorder. It was generally believed that the disease affects only adult males. Through systematic pedigree analysis, we identified 35 paediatric FD patients (age 1 to 21 years, mean 12.6 years) in 25 families. Predominant signs in this cohort were: acroparesthesia, hypohidrosis, and cornea verticillata. Neurological and psychological changes, such as tinnitus, recurrent vertigo, headache, diminished level of activity, fatigue, and depression were often observed. Angiokeratoma and gastrointestinal symptoms were frequent. Some patients also showed cardiac abnormalities. Six children and adolescents (three males and three females) over 14 years of age had renal involvement (all with proteinuria, one male had a decreased creatinine clearance of 62 ml/min). No males, but three females (1.5, 4 and 9 years of age), were free of signs and symptoms. Males (n=15, age 1 to 21 years, mean 12.4 years) and females (n=20, age 1.5 to 20 years, mean 12.7 years) showed comparable disease severity. However, the clinical courses demonstrated a wide intraand interfamilial variability and tended to be more heterogeneous in the girls. Female patients are frequently affected at an early age, not much differently than males. They should be carefully examined because most carriers are symptomatic. Conclusion: Fabry disease usually becomes clinically manifest in childhood. Renal involvement can begin in adolescence. The diagnosis is made following a high level of suspicion or systematic pedigree analysis. It is crucial for paediatric Fabry disease patients to have early access to optimal supportive symptomatic management. Enzyme replacement therapy has shown promising effectiveness in adults. Considering its widespread therapeutic and potential preventive benefits, enzyme replacement therapy should be initiated at an early stage, prior to the onset of irreversible complications.
Presymptomatic diagnosis of Fabry’s disease: a case report
Journal of Medical Case Reports, 2016
Background: Fabry's disease is a rare X-linked genetic disorder characterized by reduced levels of the αgalactosidase A enzyme. It may present with a cardiac phenotype resembling hypertrophic cardiomyopathy. However, as a specific enzyme replacement therapy is available, it remains an important differential diagnoses in patients presenting with cardiac hypertrophy. In boys, onset has been reported in early childhood with complaints initially comprising neuropathic pain, reduced sweat production, and gastrointestinal symptoms. Later the cardiac, renal, and central nervous systems may become affected. Female mutation carriers may remain asymptomatic or present at a later age with varying symptoms and clinical manifestations due to random inactivation of the X chromosome in different organs. Case presentation: Here we present a case of Fabry's disease diagnosed in the daughter of an elderly, Caucasian woman (81 years old) with late-onset cardiac conduction disease and heart failure. We discuss the implications of cascade screening relatives of elderly probands. Conclusions: Irrespective of the patient's age, physicians must be on the lookout for phenocopies when identifying patients with possibly inheritable cardiomyopathies. The specificprecisediagnosis may be crucial for the patient as well as the relatives.
Gene, 2018
Fabry disease results from deficiency of the lysosomal enzyme alphagalactosidase A. The families of 11 index cases were screened by enzyme and molecular assays. Further clinical and laboratory investigations were carried out in all cases. Including 33 new patients, a total of 28 females (Age 25,82 ± 12,1 Range 8-46) and 16 males (Age 24,56 ± 15,04 Range 2-48) were investigated. Ten different disease-causing variants were found two of them being novel. One patient had coexisting familial mediteranian fever, one had celiac disease and three had rheumatological disorders. Lipoprotein (a) levels were elevated in 17,6%, homocysteine in 22,2%, total and low density cholesterol in 12% and antithrombin 3 levels were elevated in 13,3%. One patient was found to be heterozygous for prothrombin p.G20210A disease-causing variant (5,8%) and two for factor V Leiden disease-causing variant (11,7%). Anticardiolipin IgM antibody was found to be positive in 11,7%. The patients with abnormal cranial imaging were also noticed to have additional risk factors for thrombosis. This study provides the largest data about Fabry patients from Turkey and implies that co-existing risk factors unrelated to Fabry Disease have significant association with the presence of clinical symptoms in females and might cause an early and severe clinical course in males.