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Fabry disease is a rare, life-threatening, and under-diagnosed disease, with distinctive ocular manifestations identifiable during a routine eye examination. The disease is caused by an inherited deficiency of the lysosomal enzyme alpha-galactosidase A, resulting in progressive accumulation of glycosphingolipids throughout the body. Long-term clinical manifestations include renal failure, early stroke, and cardiomyopathy. Recently, enzyme-replacement treatment has become available, heightening the importance of early diagnosis so that treatment can be initiated before irreversible organ damage. Ocular manifestations of Fabry disease include cornea verticillata (whorl-like radial lines emanating from a single vortex, visible on slit-lamp examination), distinctive lenticular opacities, and vascular tortuosity of the conjunctiva and retina. A heightened awareness of Fabry disease among ocular professionals could greatly reduce diagnostic delays and thus reduce the morbidity and mortality of the disease.
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PMID:Ocular features of Fabry disease: diagnosis of a treatable life-threatening disorder. 1857 58

Fabry disease is a complex, multisystemic and clinically heterogeneous disease with prominent urinary excretion of globotriaosylceramide (Gb(3)), the principal substrate of the deficient enzyme, alpha-galactosidase A. Some measure of specific treatment is possible with enzyme replacement therapy, which can be applied safely and effectively to Fabry patients. Incidence estimations of Fabry disease vary widely from 1:55 000 to 1:3000 male births. The true incidence is likely to be higher than originally thought, owing to the existence of milder variants of the disease. The main complications of Fabry disease are a 100-fold increased risk of ischaemic stroke, cardiac disease, a wide variety of arrhythmias, valvular dysfunction and cardiac vascular disease, as well as progressive renal failure usually associated with significant proteinuria. These clinical manifestations are non-specific and are often mistaken for symptoms of other disorders, thus complicating the confirmation of diagnosis. Other clinical features of the disease are often absent (angiokeratoma), subtle (corneal opacities and hypohidrosis), or unaccompanied by specific physical findings (acroparaesthesias) indicating the true nature of the underlying disease. We propose the hypothesis that alpha-galactosidase A deficiency is a modifiable cardiovascular risk factor in the general population. This hypothesis may be tested by a non-invasive high-risk screening protocol for Fabry patients with ischaemic strokes and a variety of cardiac, and renal complications. These patients would benefit from diagnosis, appropriate treatment, follow-up and surveillance. Early detection of Fabry patients would also benefit affected relatives, many of whom do not have a clear diagnosis of their clinical condition.
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PMID:Proposed high-risk screening protocol for Fabry disease in patients with renal and vascular disease. 1916 44

Fabry disease is a rare, X-linked inborn error of glycosphingolipid catabolism caused by a deficiency in the activity of the lysosomal enzyme, alpha-galactosidase A. In affected patients, the enzyme substrate, globotriaosylceramide (Gb3), accumulates in cells of various tissues and organs. Lysosomal accumulation of Gb3 begins in utero, and signs and symptoms of Fabry disease emerge in childhood and adolescence. The earliest presenting symptoms are typically neuropathic pain and gastrointestinal problems, which can have a substantial impact on health-related quality of life. Life-threatening major organ involvement is rare in young patients, but signs of kidney dysfunction (e.g., proteinuria), left ventricular hypertrophy, and stroke have been reported in children. There are two enzyme preparations for therapy: agalsidase alfa and beta. In two clinical trials of enzyme replacement therapy (ERT) with agalsidase alfa, including 37 children, boys demonstrated reductions in plasma Gb3 levels, and both boys and girls reported reductions in neuropathic pain and in the use of neuropathic pain medications. Heart rate variability, which is reduced in boys with Fabry disease, was statistically significantly improved with 6 months of agalsidase alfa treatment. In a single clinical study of agalsidase beta in children (n =16), skin Gb3 deposits and plasma Gb3 levels were reduced in boys. Differences exist in the administration and the safety profile of these two enzyme formulations. Follow-up of these cohorts and additional studies will be necessary to fully evaluate long-term efficacy of ERT in children with Fabry disease.
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PMID:Fabry disease in children and the effects of enzyme replacement treatment. 1924 21

Fabry disease, an X-linked disorder of glycosphingolipids that is caused by the deficiency of alpha-galactosidase A, is associated with dysfunction of many cell types and includes a systemic vasculopathy. As a result, patients have a markedly increased risk of developing small-fiber peripheral neuropathy, stroke, myriad cardiac manifestations and chronic renal disease. Virtually all complications of Fabry disease are non-specific in nature and clinically indistinguishable from similar abnormalities that occur in the context of more common disorders in the general population. Although Fabry disease was originally thought to be very rare, recent studies have found a much higher incidence of mutations of the GLA gene, suggesting that this disorder is under-diagnosed. Although the etiology of Fabry disease has been known for many years, the mechanism by which the accumulating alpha-D-galactosyl moieties cause this multi-organ disorder has only recently been studied and is yet to be completely elucidated. Specific therapy for Fabry disease has been developed in the last few years but its role in the management of the disorder is still being investigated. Fortunately, standard 'non-specific' medical and surgical therapy is effective in slowing deterioration or compensating for organ failure in patients with Fabry disease. All these aspects are discussed in detail in the present review.
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PMID:Fabry disease. 1931 41

We report a unique case with co-occurrence of Turner syndrome and Fabry disease (OMIM #301500). The latter is a rare X-linked lysosomal storage disease that is characterized by partial or complete deficiency of alpha-galactosidase A (GLA; EC 3.2.1.22) following mutations in the gene (GLA) localized at Xq22.1. Accumulation of metabolic intermediates can occur in many tissues and leads to severe morbidity, especially due to renal failure, cardiac involvement and stroke. It is well established that hemizygous male mutation carriers with Fabry disease are generally more severely affected than heterozygous female mutation carriers, but disabling clinical features and disease progression often occur in female Fabry patients as well. The majority of this patient's cells are of the 45,X type, making her a hemizygous GLA mutation carrier displaying a very severe Fabry disease phenotype.
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PMID:Fabry disease in a patient with Turner syndrome. 1934 33

Since the foundations laid by Sacco and Mohr in 1989, from the Stroke data bank, cryptogenic infarctions have had a predominant place among the causes of ischemic strokes. In that study, they accounted for approximately 40% of the stroke causes. Cryptogenic infarctions are infarctions without a defined cause, despite a complete work-up; they differ from infarctions of undetermined causes, which may involve overlapping causes or an incomplete investigation. The size of this group will probably shrink as knowledge advances. Patent foramen ovale (PFO), with or without a septal aneurysm, is more frequent in patients with a cryptogenic infarction. Transesophageal echocardiography is the reference examination for screening for these abnormalities. A meta-analysis of several case-control studies showed a significant association between PFO and stroke in subjects younger than 55 years. For now, these septal abnormalities constitute a risk factor but not a cause. Complex aortic atheroma affecting area upstream of the left subclavian artery may be a source of cerebral embolisms in some conditions. The prevalence of this disease increases with age. It is identified most frequently in patients older than 60 years with a cryptogenic infarction. The thickness of the atheromatous plaque determines whether it is a risk factor or a cause. Recent stroke classifications do not consider carotid atheromatous lesions less than 50% to be a source of ischemic stroke. Nonetheless some studies identify moderate stenosis of the carotid artery more frequently in infarctions of unknown causes than in other categories. The increased risk of cerebral infarction when parents and homozygous twins have a history of stroke suggests that there may be genetic causes that have not yet been detected. An unknown genetic cause would thus be included in the infarctions of unknown causes. A recent study tested for Fabry disease in young patients with a cryptogenic infarction: 4.9% of the men and 2.4% of the women had a functional mutation of the alpha-galactosidase gene. These findings must be confirmed. Some studies suggest an association between cryptogenic infarction and hereditary thrombophilias. Nonetheless the risk attributable to these thrombophilic disorders is slight and the discovery may be only a coincidence. The work described above shows the importance of stratification in the identification of stroke causes: age older or younger than 55/60 years, type of interatrial abnormality (PFO and aneurysms of the interatrial septum), type of atheroma of the aortic arch (more or less than 4mm). They also show the difficulty involved in attributing cause to an identified abnormality: is carotid stenosis of less than 50% a marker of atherosclerosis or also a cause of stroke? To continue improving our understanding of the mechanisms of strokes, new investigational techniques are under evaluation. They include magnetic resonance imaging (MRI), computed tomographic angiography (CT), positron emission tomography (PET) of carotid plaque and of the aortic arch, transcranial Doppler, cardiac recording by telemetry, and even new biological assays.
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PMID:[Cryptogenic cerebral infarction: from classification to concept]. 1939 32

Fabry disease is an X-linked recessive glycolipid storage disease. It is caused by deficiency of the lysosomal enzyme alpha-galactosidase A and leads to the accumulation of the enzyme substrate, globotriasylceramide (Gb3) in many tissues including endothelial cells, pericytes and smooth muscle cells of blood vessels, renal epithelial cells, cardiac myocytes and numerous neuronal cells. In this report, we present 20-year-old male patient with ischemic stroke in pons. The case had previously been misdiagnosed as polimyositis and vasculitis. Angiokeratomas, neuropathic pain and ischemic stroke in young age suggested a Fabry disease. The diagnosis was confirmed biochemically and genetically. All young adults with stroke, especially if they have additional symptoms like angiokeratomas, proteinuria, neuropathic pain in toes and fingers should be tested for Fabry disease.
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PMID:Neurological manifestation of Fabry disease--a case report. 2012 Apr 9

Fabry's disease is an X-linked lysosomal storage disorder resulting from alpha-galactosidase A deficiency. Although ischemic stroke is recognized as an important manifestation of Fabry's disease, hemorrhagic stroke is considered to be rare. Here, we report our recent clinical experience with three hemizygous male patients with Fabry's disease who developed cerebral hemorrhage. One patient had classic type Fabry's disease with p.Ala37Val mutation and others had cerebrovascular variant with p.Glu66Gln mutation. Degeneration of the cerebral small arteries secondary to deposition of glycosphingolipids and aging, in addition to hypertension and antiplatelet/anticoagulant agents, are considered to be contributing factors for hemorrhage. Fabry's disease is frequently associated with not only ischemic but also hemorrhagic stroke, especially in elderly patients.
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PMID:Cerebral hemorrhage in Fabry's disease. 2030 Jan 24

Fabry disease is caused by intracellular accumulation of glycosphingolipids in various tissues, secondary to mutations in the GLA gene (Xq22). Classically described as affecting hemizygous males with no residual alpha-galactosidase A activity, it is now known to affect both sexes, with later and less severe manifestations in females. The manifestations of this disease are systemic: neurological, cutaneous (angiokeratomas), renal, cardiovascular (left ventricular hypertrophy, valve thickening or rhythm disturbances), cochlear-vestibular, and cerebrovascular. In the absence of treatment there is progressive damage to vital organs with renal failure, stroke, heart failure or rhythm perturbations, leading to severe impairment of quality of life as well as reduced life expectancy. We describe the case of a female patient with a history of cryptogenic ischemic stroke at the age of 38 years and chronic renal failure with proteinuria, who presented to the emergency room with atrial fibrillation. The echocardiogram revealed concentric left ventricular hypertrophy, diastolic dysfunction and decreased longitudinal strain in the basal septum. In the context of a screening protocol, she was diagnosed with Fabry disease and a previously undescribed mutation was identified.
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PMID:[Description of a new mutation in a female patient with Fabry disease]. 2211 30

Fabry disease (FD) is an X-linked inherited disease due to alpha-galactosidase A (alpha-Gal A) deficiency and characterized by lysosomal storage of globotriaosylceramide (Gb3) and related neutral glycosphingolipids. Storage of these substrates results in multisystem manifestations, including renal failure, cardiomyopathy, premature myocardial infarctions, stroke, chronic neuronopathic pain, gastrointestinal disturbances, and skin angiokeratoma. Enzyme replacement therapy (ERT) with recombinant human alpha-galactosidase A (rh-alpha-Gal A) is now available for the treatment of FD and in most patients results in clinical improvement or stabilization. However, ERT efficacy may vary in different tissues and its long-term effects remain to be defined. As a strategy to improve the efficacy of ERT, we tested the combination of rh-alpha-Gal A with the chaperone molecule 1-deoxynojirimycin (DGJ) in cultured FD fibroblasts with negligible residual enzyme activity. Compared to the effects of rh-alpha-Gal A alone, co-administration of DGJ and rh-alpha-Gal A resulted in better correction (4.8 to 16.9-fold) of intracellular alpha-Gal A activity, and increased amounts of the enzyme within the lysosomal compartment. The clearance of lyso-Gb3, one of the substrates stored in FD and a potent inhibitor of alpha-Gal A, was also significantly improved with the co-administration of DGJ and rh-alpha-Gal A. This study provides additional evidence for a synergistic effect between ERT and pharmacological chaperone therapy and supports the idea that the efficacy of combination protocols may be superior to ERT alone.
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PMID:Synergy between the pharmacological chaperone 1-deoxygalactonojirimycin and the human recombinant alpha-galactosidase A in cultured fibroblasts from patients with Fabry disease. 2397 50


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