We searched PubMed (past 10 years) for the terms “Fabry disease”, alone and in combination with “clinical manifestations” or “enzyme replacement therapy”. We translated all publications not in English that resulted from this search. We mostly selected publications in the past 5 years, including major randomised trials, but additional relevant and frequently referenced older publications were also reviewed. Review articles were also included, because of their comprehensive overviews of
SeriesFabry's disease
Introduction
Fabry's disease (Anderson–Fabry's disease, Online Mendelian Inheritance in Man [OMIM] number 301500) is an X-linked lysosomal storage disorder initially described in 1898, which is caused by deficiency of α-galactosidase A.1 Usual onset of first symptoms is in childhood. By middle age, life-threatening complications often develop in untreated patients. The life expectancy in untreated men is reduced by about 20 years from that of the general population of 50 years, with a steep decline in survival after 35 years.2 Women can also have symptoms, but onset is generally later than for men and life expectancy is reported to be reduced by about 15 years.3
Section snippets
Epidemiology
The incidence of Fabry's disease has been estimated at one in 40 000 to one in 117 000 worldwide.4 We do not know of any ethnic predisposition, but regional pockets with increased incidence can occur because of founder effects, as has been documented in Nova Scotia, Canada, and West Virginia, USA. Fabry's disease is probably underascertained, because presenting symptoms are non-specific. Residual enzyme activity might lead to slow progression of the disease and result in the so-called cardiac
Pathophysiology
Deficiency of α-galactosidase A leads to storage of neutral glycosphingolipids, particularly globotriaosylceramid and galactosylceramide, in many tissues and cell types. As little as 5–10% of residual enzyme activity seems to be sufficient to prevent clinically significant accumulation of globotriaosylceramid.11 Progressive storage of these molecules eventually leads to cellular dysfunction, which might in turn trigger inflammation or fibrosis, or both. These processes lead to organ dysfunction
Clinical presentation
Progression of clinical symptoms in Fabry's disease can be divided conceptually into three consecutive age periods. Although the disease process begins early with evidence of storage even in the prenatal period, symptoms do not develop until early childhood.25
Early symptoms in children include burning pain in the hands and feet, hypohydrosis, nausea, abdominal pain, postprandial diarrhoea, poor growth, and school difficulties (primarily frequent absences, poor participation especially in
Diagnosis
Diagnosis is frequently delayed by several years because of the non-specific nature of the presenting complaints.26, 27, 28 In children the presence of acute, unexplained episodes of pain or chronic pain in the limbs, exercise intolerance, unexplained gastrointestinal disturbances, hypohidrosis, and angiokeratomas are the most common presenting signs and symptoms (figure 3). Characteristic corneal lesions are seen in most affected children even early in the disease course. Mild proteinuria
Management
Theoretically, reversal of the abnormal accumulation of sphingolipids from target organs should lead to clinical improvement or stabilisation.85 Enzyme replacement therapy has now been available for several years and received approval in Europe in 2001 and the USA in 2003. Additionally, other treatment options are being studied. The advent of specific treatment has increased the need for early recognition to help treatment and delay or prevent complications.
In Europe, two preparations of the
Conclusion
More data are needed to document long-term treatment outcomes, which would ideally come from a combination of long-term observational studies and well designed randomised trials. Studies are needed to evaluate the effect of treatment on various aspects of the disease process, different dose regimens of the two available preparations, and their comparison at the recommended doses and equivalent doses. Studies of the effect of treatment at different stages of the disease are also needed,
Search strategy and selection criteria
References (103)
- et al.
High incidence of later-onset fabry disease revealed by newborn screening
Am J Hum Genet
(2006) - et al.
Prevalence of Fabry disease in patients with cryptogenic stroke: a prospective study
Lancet
(2005) - et al.
Middelheim Fabry Study (MiFaS): a retrospective Belgian study on the prevalence of Fabry disease in young patients with cryptogenic stroke
Clin Neurol Neurosurg
(2007) - et al.
Alpha-galactosidase A in vascular disease
Trends Cardiovasc Med
(2007) - et al.
The cerebral vasculopathy of Fabry disease
J Neurol Sci
(2007) - et al.
Diagnosis and management of kidney involvement in Fabry disease
Adv Chronic Kidney Dis
(2006) - et al.
Comparative evaluation of alpha-galactosidase: a infusions for treatment of Fabry disease
Genet Med
(2003) - et al.
Heterozygous Fabry women are not just carriers, but have a significant burden of disease and impaired quality of life
Genet Med
(2007) - et al.
Females with Fabry disease frequently have major organ involvement: lessons from the Fabry Registry
Mol Genet Metab
(2008) - et al.
Fabry disease in childhood
J Pediatr
(2004)
Clinical benefit of enzyme replacement therapy in Fabry disease
Kidney Int
Fabry disease: guidelines for the evaluation and management of multi-organ system involvement
Genet Med
Prevalence of uncontrolled hypertension in patients with Fabry disease
Am J Hypertens
Cardiovascular manifestations in Fabry disease: a clinical and echocardiographic study
Heart Lung Circ
Impact of enzyme replacement therapy on cardiac morphology and function and late enhancement in Fabry's cardiomyopathy
Am J Cardiol
CNS manifestations of Fabry's disease
Lancet Neurol
Polyneuropathies in teenagers: a clinicopathological study of 45 cases
Neuromuscul Disord
Gastrointestinal symptoms in 342 patients with Fabry disease: prevalence and response to enzyme replacement therapy
Clin Gastroenterol Hepatol
Gastrointestinal manifestations of Fabry disease: clinical response to enzyme replacement therapy
Mol Genet Metab
Comparison of health-related quality of life between heterozygous women with Fabry disease, a healthy control population, and patients with other chronic disease
Genet Med
Enzyme replacement therapy in Fabry disease patients undergoing dialysis: effects on quality of life and organ involvement
Am J Kidney Dis
Quantitative dysmorphology assessment in Fabry disease
Genet Med
Simple criteria for differentiation of Fabry disease from amyloid heart disease and other causes of left ventricular hypertrophy
Int J Cardiol
Fabry's disease cardiomyopathy: echocardiographic detection of endomyocardial glycosphingolipid compartmentalization
J Am Coll Cardiol
Enzyme therapy for Fabry disease: neutralizing antibodies toward agalsidase alpha and beta
Kidney Int
A phase 1/2 clinical trial of enzyme replacement in fabry disease: pharmacokinetic, substrate clearance, and safety studies
Am J Hum Genet
Influence of antibody formation on reduction of globotriaosylceramide (GL-3) in urine from Fabry patients during agalsidase beta therapy
Mol Genet Metab
Angiokeratoma corporis diffusum—Fabry disease: historical review from the original description to the introduction of enzyme replacement therapy
Acta Paediatr Suppl
Anderson-Fabry disease: clinical manifestations and impact of disease in a cohort of 98 hemizygous males
J Med Genet
Anderson-Fabry disease: clinical manifestations and impact of disease in a cohort of 60 obligate carrier females
J Med Genet
Fabry disease defined: baseline clinical manifestations of 366 patients in the Fabry Outcome Survey
Eur J Clin Invest
Cardiac involvement in Fabry disease
Acta Paediatr Suppl
The heart in Anderson-Fabry disease and other lysosomal storage disorders
Heart
Results of a nationwide screening for Anderson-Fabry disease among dialysis patients
J Am Soc Nephrol
Narrative review: Fabry disease
Ann Intern Med
Evaluation of peripheral and autonomic nerve function in Fabry disease
Acta Paediatr Suppl
Natural history of the cerebrovascular complications of Fabry disease
Acta Paediatr Suppl
CNS pathology and vascular/circulatory abnormalities in Fabry disease
Acta Paediatr Suppl
Staging of Fabry disease using renal biopsies
Clin Ther
Renal pathology in Fabry disease
J Am Soc Nephrol
Genotype and phenotype in Fabry disease: analysis of the Fabry Outcome Survey
Acta Paediatr Suppl
Disease manifestations and X inactivation in heterozygous females with Fabry disease
Acta Paediatr Suppl
Relationship between X-inactivation and clinical involvement in Fabry heterozygotes. Eleven novel mutations in the alpha-galactosidase: a gene in the Czech and Slovak population
J Mol Med
Fabry disease: molecular studies in Italian patients and X inactivation analysis in manifesting carriers
J Med Genet
Manifestations of Fabry disease in placental tissue
J Inherit Metab Dis
Natural history of Fabry disease in females in the Fabry Outcome Survey
J Med Genet
Clinical manifestations of Fabry disease in children: data from the Fabry Outcome Survey
Acta Paediatr
Fabry disease: baseline medical characteristics of a cohort of 1765 males and females in the Fabry Registry
J Inherit Metab Dis
The early clinical phenotype of Fabry disease: a study on 35 European children and adolescents
Eur J Pediatr
Clinical results of enzyme replacement therapy in Fabry disease: a comprehensive review of literature
Int J Clin Pract
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