Cataract associated with a metabolic disease
-Rare eye disease
-Rare genetic disease
Developmental anomaly of metabolic origin
-Rare developmental defect during embryogenesis
-Rare genetic disease
Genetic skin vascular disease
-Rare genetic disease
Lysosomal disease with hypertrophic cardiomyopathy
-Rare cardiac disease
-Rare genetic disease
Lysosomal disease with restrictive cardiomyopathy
-Rare cardiac disease
-Rare genetic disease
Metabolic disease with corneal opacity
-Rare eye disease
-Rare genetic disease
Nephropathy secondary to a storage or other metabolic disease
-Rare genetic disease
-Rare renal disease
Rare hereditary metabolic disease with peripheral neuropathy
-Rare genetic disease
-Rare neurologic disease
Skin vascular disease
-Rare skin disease
Sphingolipidosis
-Rare genetic disease
Sphingolipidosis with epilepsy
-Rare neurologic disease
Syndromic lymphedema
-Rare circulatory system disease
-Rare developmental defect during embryogenesis
-Rare genetic disease
-Rare skin disease
Comment:
Heterozygous females were thought to be asymptomatic carriers. However, it is now well acknowledged that heterozygous females can also be affected and may develop the full phenotype of disease manifestation, even though the aggravation of the disease occurs later in life. (PMID:25987173)
Females are affected because there is no cross-correction between cells with normal α-galactosidase A activity (mutated X chromosome is inactivated) and enzyme deficient cells (non-mutated X chromosome is inactivated). The expression of the disease in female patients depends on the particular GLA mutation and especially on the pattern of X chromosome inactivation in each organ. Females can develop any of the complications that are seen in males, including strokes, cardiac disease and progressive renal insufficiency. However, in general, the clinical abnormalities are more variable, less severe and of later onset compared to the males with similar GLA mutations. (PMID:19318041)
The phenotypic variability of two male patients is not related to differences in α-GAL enzymatic activity: though both have no enzymatic activity, the youngest shows severe symptoms, while the eldest is asymptomatic. It is noticeable that for two female patients with the M51I mutation the initial clinical diagnosis was different from Fabry disease (FD). One of them was diagnosed with Familial Mediterranean Fever, the other with Multiple Sclerosis. Overall, this study confirms that the extreme variability of the clinical manifestations of FD is not entirely attributable to different mutations in the GLA gene and emphasizes the need to consider other factors or mechanisms involved in the pathogenesis of Fabry Disease. (PMID:25977923)
Fabry disease is an X-linked inborn error of glycosphingolipid catabolism resulting from deficient or absent activity of the lysosomal enzyme alpha-galactosidase A. This enzymatic defect leads to the systemic accumulation of globotriaoslyceramide (Gb3) and related glycosphingolipids in the ... Fabry disease is an X-linked inborn error of glycosphingolipid catabolism resulting from deficient or absent activity of the lysosomal enzyme alpha-galactosidase A. This enzymatic defect leads to the systemic accumulation of globotriaoslyceramide (Gb3) and related glycosphingolipids in the plasma and cellular lysosomes of vessels, nerves, tissues, and organs throughout the body (Nance et al., 2006). The disorder is a systemic disease, manifest as progressive renal failure, cardiac disease, cerebrovascular disease, small-fiber peripheral neuropathy, and skin lesions, among other abnormalities (Schiffmann, 2009). An atypical variant of Fabry disease has been reported in which cardiac disease, specifically left ventricular hypertrophy, with or without renal failure, develops in the sixth decade of life. These patients have residual GLA activity (Nakao et al., 1995; Nakao et al., 2003). Although previously considered an X-linked recessive disorder, Wang et al. (2007) found that heterozygous women with Fabry disease experience significant life-threatening conditions requiring medical treatment and intervention. Thus, heterozygous Fabry women should not be called carriers, as this term underestimates the seriousness of the disease in these patients. Clarke (2007) and Schiffmann (2009) provided detailed reviews of Fabry disease.
Kint (1970) showed that the activity of alpha-galactosidase is deficient in leukocytes of male patients with Fabry disease and that affected females can be identified by this method. Moser (1983) considered the urinary trihexoside assay, described by Cable ... Kint (1970) showed that the activity of alpha-galactosidase is deficient in leukocytes of male patients with Fabry disease and that affected females can be identified by this method. Moser (1983) considered the urinary trihexoside assay, described by Cable et al. (1982), to be the most reliable way to identify individuals with Fabry disease. In a Nova Scotia kindred in which 30 males had Fabry disease and there were 50 possible females with the mutation, Kirkilionis et al. (1991) used cDNA analysis of a polymorphic NcoI site 3-prime to the gene to identify females with the mutation. All of 17 females with the mutation examined were identified, including 6 who were not identified by enzyme assay. Germain et al. (1996) used the fluorescence-assisted mismatch analysis (FAMA) method to screen the GLA gene rapidly in patients with Fabry disease. Mutations were identified in affected members of 9 unrelated kindreds. Among the 7 previously undescribed sequence changes, 3 were obviously pathogenic because they led to premature protein termination. The other 4, a splice site mutation and 3 missense mutations, were the only changes found upon complete scanning of the gene and its promoter. The authors claimed that FAMA detected female heterozygotes more dependably than direct sequencing, and thus provided a valuable diagnostic test in connection with genetic counseling since heterozygotes can be asymptomatic and their enzymatic values within the normal range. Germain and Poenaru (1999) reported further experience in the use of the fluorescent chemical cleavage of mismatches in the detection of mutations and identification of heterozygotes. Spada et al. (2006) reported the screening of 37,104 consecutive newborn males for Fabry disease by determination of the alpha-Gal A activity in dried blood spots. Twelve neonates, or 1 in approximately 3,100 males, had deficiency of enzyme activity and GLA mutations. Molecular modeling studies and in vitro studies of mutant enzyme activity yielded a ratio of 11:1 of patients with the later-onset:classic phenotypes. The higher incidence of the later-onset phenotype in patients raised ethical issues related to when screening should be performed, in the neonatal period or at early maturity, perhaps in conjunction with screening for other treatable adult-onset disorders. Using structural brain MRI and brain MR angiography to evaluate 25 patients with Fabry disease, Fellgiebel et al. (2009) found that patients with the disorder had significantly enlarged diameters of several cerebral arteries, including the basilar, middle cerebral, posterior cerebral, and carotid compared to controls. A total of 87% of individuals with Fabry disease could be correctly classified as affected using basilar artery diameters alone (sensitivity of 95%; specificity of 83%). The difference in basilar artery diameter was clearly superior to white matter lesion load in distinguishing between patients and controls. Fellgiebel et al. (2009) concluded that basilar artery diameters as measured by MR angiography could be used for early detection and monitoring of brain involvement in patients with Fabry disease.
In his first paper on this subject, Fabry (1898) called the skin lesions 'purpura papulosa haemorrhagica Hebrae,' suggesting that they had previously been described by Hebra, the famous Austrian dermatologist. Affected individuals had painful crises in the extremities, ... In his first paper on this subject, Fabry (1898) called the skin lesions 'purpura papulosa haemorrhagica Hebrae,' suggesting that they had previously been described by Hebra, the famous Austrian dermatologist. Affected individuals had painful crises in the extremities, thought to result from lipid changes in ganglion cells of the autonomic nervous system. Attacks of pain in the abdomen may have been misdiagnosed as appendicitis or other surgical emergencies. Vascular lesions of lipid nature occurred at other sites such as the ocular fundi and kidney. Renal failure was the usual cause of death. Hamburger et al. (1964) described a familial nephropathy, manifested clinically by proteinuria and renal insufficiency. Renal biopsy showed that the epithelial cells of the glomerular tufts and to a lesser extent the tubular epithelial cells, glomerular endocapillary cells and arteriolar muscular cells were severely deformed with a large amount of cytoplasmic inclusion material appearing lipoid in nature. The mother's father died of uremia. Skin lesion may be lacking even in patients with severe visceral manifestations (Johnston, 1967). Furthermore, identical angiokeratoma skin lesions occur in other lysosomal disorders: (see, e.g., Patel et al., 1972 and Loonen et al., 1974). Flynn et al. (1972) described a family without skin lesions. One affected male had severe enteropathy. Franceschetti et al. (1969) reexamined a family with 'cornea verticillata' reported by Gruber (1946) and showed that Fabry disease was responsible for the corneal change. The extent of involvement of the cornea was about the same in males and females, thus allowing affected females to be identified. The corneal condition was formerly called Fleischer vortex dystrophy, or whorl-like corneal dystrophy. Stark (1999) noted that the antimalarial drug atabrine and the antiarrhythmic drug amiodarone can also cause these changes. Mastropasqua et al. (2006) found that although Fabry disease-related corneal verticillata attributable to glycosphingolipid accumulation was considered to be primarily a corneal disease, in vivo confocal microscopy demonstrated structural alterations throughout the entire ocular surface epithelia. Different types of corneal epithelial lesions were observed in hemizygous and heterozygous patients. In a period of a few months at a Montreal hospital, Clarke et al. (1971) saw 2 men with Fabry disease with clear corneas and without skin lesions, suggesting that it may be a more frequent cause of proteinuria or renal failure than realized. Romeo et al. (1972) studied one of Clarke's cases and concluded that enzymatically there were differences from the classic cases. A difference from the usual form of Fabry disease is suggested by the fact that leukocyte alpha-galactosidase deficiency was only partial rather than complete (Kint, 1970). Halsted and Rowe (1975) described a 59-year-old man with Fabry disease. In addition to his unusually advanced age, he had celiac sprue (212750), which may have been related to the presence of the HLA-8 antigen. Roudebush et al. (1973) may have reported the first cases of 'abbreviated PR interval' in Fabry disease, which may be related to to the development of tachyarrhythmias and sudden death (Efthimiou et al., 1986). Sakuraba et al. (1986) reported a high incidence of mitral valve prolapse in male Fabry patients as well as female patients. Ko et al. (1996) described an 'oligosymptomatic' variant of Fabry disease. A renal biopsy performed for evaluation of trace proteinuria revealed histologic and ultrastructural findings compatible with Fabry disease in a 34-year-old man with no history of renal disease in other family members. Biopsy of a few initially unrecognized, scattered, dark-pinkish scrotal papules showed typical angiokeratoma. Alpha-galactosidase was markedly decreased in urine and plasma. MacDermot et al. (2001) studied 98 males with Fabry disease. Mean age at diagnosis was 21.9 years, and the median survival was 50 years. Neuropathic pain was present in 93 individuals (77%), with a mean pain score of 5 (scale from 0 to 10). Cerebrovascular complications were present in 24.2% of individuals studied and renal failure in 30%. High frequency sensorineural deafness was confirmed in 78% of audiograms. Attendance at school, sports, and social activities were significantly affected by Fabry disease and only 46 patients (56.6%) were employed. Psychosexual function was affected by the presence of genital angiokeratoma, genital pain, and impotence. Branton et al. (2002) reviewed the medical records of 105 male patients with Fabry disease. Diagnosis of Fabry disease occurred later in patients without a known family history. Fifty percent of patients developed proteinuria by age 35 years and chronic renal insufficiency by age 42. Detectable residual alpha-galactosidase A activity was associated with a slower progression of Fabry renal disease, and with lower scores for renal histologic damage and renal content of globotriaosylceramide. Conservative mutations in the GLA gene were also associated with a slower progression in Fabry renal disease. Senechal and Germain (2003) reviewed the functional and anatomical cardiac manifestations in 20 hemizygous male patients with Fabry disease. Left ventricular hypertrophy and/or concentric remodeling were found in 60% of cases; structural changes in mitral and aortic valves in 25% and 10%, respectively; and short PR interval in 40%. Rolfs et al. (2005) found that 21 (4.9%) of 342 males and 7 (2.4%) of 289 females with cryptogenic stroke had biologically significant mutations in the GLA gene. The mean age at onset of symptomatic cerebrovascular disease was 38.4 and 40.3 years in the men and women, respectively. Approximately 30% had classic manifestations of Fabry disease. Due to the high frequency of Fabry disease (4%, 28 of 721) in this cohort of stroke patients with cryptogenic stroke aged between 18 and 55 years, Rolfs et al. (2005) suggested that Fabry disease should be considered in young patients with unexplained stroke. Nance et al. (2006) reported a 34-year-old man who presented with chronic exercise-induced pain, cramps, and fasciculations of the legs and feet. His mother was similarly affected. Alpha-glucosidase activity was 8.8% and 13.4% of normal, respectively. Moore et al. (2007) provided a review of the cerebral vasculopathy in Fabry disease. Patients presented more commonly with radiologic findings consistent with small-vessel disease rather than large-vessel disease, although both may occur. The posterior circulation was more commonly affected. The pathomechanism is believed to result from a combination of abnormalities of the vessel wall, blood components, such as pro- and anti-coagulants, and abnormal hemodynamics or blood flow. Schiffmann (2009) noted that patients with Fabry disease have a 20-fold increased risk of ischemic stroke and transient ischemic attacks compared to the general population. To evaluate life expectancy and cause of death among patients with Fabry disease, Waldek et al. (2009) examined data from 2,848 patients in the Fabry Registry. Life expectancy at birth was compared with that of the United States general population. As of August 2008, 75 of 1,422 males and 12 of 1,426 females in the Fabry Registry were reported to have died. The 87 deceased patients were diagnosed at a much older age than other patients in the Fabry Registry: median age at diagnosis was 40 versus 24 years in males and 55 versus 33 years in females. Life expectancy of males with Fabry disease was 58.2 years, compared with 74.7 years in the general population of the United States. The life expectancy of females with Fabry disease was 75.4 years, compared with 80.0 years in the United States general population. The most common cause of death among both genders was cardiovascular disease. Most (57%) patients who died of cardiovascular disease had previously received renal replacement therapy. Waldek et al. (2009) concluded that most deceased Fabry Registry patients exhibited serious cardiac and renal dysfunction, and that late diagnosis may have contributed to the early deaths of these patients. Mehta et al. (2009) reported the clinical outcomes of 1,453 Fabry patients (699 males and 754 females) from 19 countries participating in the Fabry Outcome Survey (FOS). The most frequently reported signs and symptoms were neurologic, affecting 75% of males and 61% of females. Renal failure was present in 134 males and 21 females: 89 males and 5 females had end-stage renal disease at a mean age of 32.3 and 23.3 years, respectively. Cardiac manifestations were recorded in 422 male and 376 female patients: 284 males and 180 females had left ventricular hypertrophy with onset at a mean age of 28.7 and 34.1 years, respectively. Cerebrovascular events occurred with approximately the same frequency in males and females (25% and 21%, respectively). Stroke was reported in 39 females and 63 males at mean ages of 51.4 and 39.2 years, respectively. Forty-two patients had died, including 35 males and 7 females at a mean age of 51.8 and 64.4 years, respectively. The primary cause of death in both male and female patients was cardiac disease, reported in 34% and 57%, respectively. This was in contrast to the principal causes of death among 181 affected relatives of Fabry patients who died before 2001: the most common causes of death were due to renal failure in males (42%) and cerebrovascular disease in females (25%). Overall, the data suggested that renal disease as a cause of death in patients with Fabry disease is decreasing while cardiac disease is increasing. This pattern probably reflects improvements in the management of renal disease in patients with Fabry disease. Testai and Gorelick (2010) reviewed the pathophysiology of stroke in patients with Fabry disease. Population studies had estimated that Fabry disease is responsible for 1.2% of cryptogenic strokes in patients younger than 55 years, and women are more likely to be affected than men (27% vs 12%). Stroke may result from both cardiac (hypertrophy, arrhythmia) or vascular (stenosis, vessel occlusion, vessel dilation) factors. The posterior circulation is most commonly affected. Brain imaging may show progressive white matter lesions. - Cardiac Variant of Fabry Disease The observations of Ogawa et al. (1990), Elleder et al. (1990), Nagao et al. (1991), and von Scheidt et al. (1991) indicated that manifestations of Fabry disease can be limited to the heart. These authors suggested that Fabry disease should be considered in patients who have cardiac symptoms, such as angina, exercise intolerance, and electrocardiographic changes, but normal coronary arteries, heart size, and hemodynamic findings. Cases of Fabry disease limited to the cardiac manifestation may be identified by ultrastructural examination of endomyocardial biopsy specimens or, less invasively, by determining the plasma GLA activity in male patients with unexplained cardiac symptoms. The oldest of the patients reported with this form of the disease was a Japanese patient who died at the age of 71 years (Ogawa et al., 1990). Nagao et al. (1991) reported 2 unrelated males who developed hypertrophic cardiomyopathy after the age of 50 as their first manifestation of Fabry disease. Von Scheidt et al. (1991) reported a 54-year-old man with the cardiac variant of Fabry disease confirmed by genetic analysis (M296V; 300644.0005). The patient had 'crescendo angina,' relieved by nitroglycerin, as well as electrocardiographic changes, but normal cardiac chamber size and normal systolic and diastolic function by echocardiogram. Cardiac catheterization showed no stenoses of the extramural coronary arteries. Diagnosis of Fabry disease was made by endomyocardial biopsy. Light-microscopic examination showed that approximately half the myocytes contained a centrally stored foamy material that stained metachromatically. By electron microscopy, typical myelin-figure-like concentric lamellar inclusions in lysosomes were observed. Most remarkably, the endothelial cells of the myocardial capillaries were not involved and no changes were observed in specimens of skeletal muscle, liver, rectum, and skin, including small blood vessels and nerves. Nakao et al. (1995) found that 7 of 230 unrelated Japanese men with left ventricular hypertrophy had the atypical variant of Fabry disease. These 7 unrelated men, ranging in age from 55 to 72 years, did not have angiokeratoma, acroparesthesias, hypohidrosis, or corneal opacities. Endomyocardial biopsy revealed marked sarcoplasmic vacuolization in all 5 patients examined. Electron microscopy, performed on tissues from 4 of these patients, revealed typical lysosomal inclusions with a concentric lamellar configuration. Two patients had novel missense mutations in the GLA gene (300644.0051; 300644.0052). The remaining 5 patients had no mutations in the coding region of the GLA gene; however, in addition to low plasma alpha-galactosidase activity, GLA mRNA was markedly lower than normal. Elleder et al. (1994) demonstrated storage material in the external arachnoidal epithelium of the leptomeninges in a case of cardiocyte-restricted Fabry disease. The patient, a 65-year-old male with Fabry disease who died from bile duct carcinoma, showed only cardiac symptoms and signs premortem. This pattern contrasted with the generalized leptomeningeal storage seen in typical Fabry disease. - Female Fabry Patients Romeo and Migeon (1970) reported genetic inactivation of the alpha-galactosidase locus in females patients with Fabry disease, consistent with lyonization. Bird and Lagunoff (1978) reported 2 adult sisters with Fabry disease. They both had episodic and permanent neurologic deficits, including vertigo, tinnitus, long tract motor signs, and bladder incontinence. Broadbent et al. (1981) reported a 58-year-old female patient who had cardiac enlargement and developed heart failure. Endomyocardial biopsy showed cellular changes consistent with Fabry disease. The authors postulated unfavorable lyonization of the mutant X chromosome in cardiac tissue. Rodriguez et al. (1985) reported a 42-year-old woman with Fabry disease who had persistent proteinuria. Mutoh et al. (1988) described an unusual degree of autonomic dysfunction, manifested by severe orthostatic hypotension, in a 21-year-old female patient. Hasholt et al. (1990) described a girl in whom Fabry disease was suspected at the age of 18 years because of corneal opacities and tortuous retinal vessels. She had had attacks of high fever, arthralgia, and abdominal pain. Studies indicated that she suffered from a new mutation for Fabry disease; she was heterozygous. Hillsley et al. (1995) described a 74-year-old woman with restrictive cardiomyopathy complicating conventional coronary artery disease that had been treated with angioplasty and with coronary artery bypass grafting. MacDermot et al. (2001) reported clinical manifestations and impact of disease in 60 females with Fabry disease. The median cumulative survival was 70 years, representing an approximate reduction of 15 years from the general population. Six of 32 women had renal failure, 9 of 32 (28%) died of cerebrovascular complications, and 42 (70%) had experienced neuropathic pain. Twenty (30%) female patients had some serious or debilitating manifestation of Fabry disease. Whybra et al. (2001) performed a comprehensive clinical evaluation on 20 females with Fabry disease. In addition to skin manifestations, various other clinical manifestations of the disease were present, including acroparesthesia, kidney dysfunction, cerebrovascular disease, and gastrointestinal and heart problems. Pruss et al. (2006) reported a 50-year-old woman who presented with a 10-year history of paroxysmal rotational vertigo without hearing loss or tinnitus. Brain MRI revealed megadolichobasilar artery and white matter lesions. Due to a positive family history of Fabry disease, molecular analysis was performed, and a mutation was found in the GLA gene. She displayed cornea verticillata but neither angiokeratoma nor acroparesthesia. Pruss et al. (2006) postulated that the vertigo resulted from megadolichobasilar compression of the vestibulocochlear nerve. Kim et al. (2007) reported a 38-year-old woman with Fabry disease who had acroparesthesias and anhidrosis since adolescence. She later developed gastrointestinal bloating and interstitial lung disease with progressive dyspnea requiring supplemental oxygen at all times. High-resolution CT scans showed regions of both abnormally dense and lucent lung parenchyma, reflecting a combination of ground-glass opacity and air trapping, most conspicuous in the upper lobes. There was also evidence of pulmonary hypertension. Skin examination showed cutaneous angiokeratomas and digital clubbing. Treatment with enzyme replacement therapy resulted in significant pulmonary and gastrointestinal improvement within several months. In a review of the medical records of 44 heterozygous female patients with Fabry disease, Wang et al. (2007) concluded that female Fabry patients experience significant multisystemic disease and reduced quality of life. Acroparesthesias were the first reported symptom in 76%; most reported the first symptoms during the first 2 decades of life. Clinical features and findings included fatigue, exercise intolerance, stroke, obstructive pulmonary disease, angina, renal disease, gastrointestinal complaints, and decreased vibration sense. Eleven patients were treated with enzyme replacement therapy. Wang et al. (2007) suggested that Fabry disease should not be considered an X-linked recessive disorder and that heterozygous Fabry women should not be called carriers because they experience significant life-threatening conditions requiring medical treatment and intervention.
Among 32 children and 78 adults with Fabry disease, Auray-Blais et al. (2008) identified 35 different mutations in the GLA gene, including missense (76.4%), nonsense (16.4%), frameshift (3.6%), and splice site defects (3.6%). Forty-one of the patients were ... Among 32 children and 78 adults with Fabry disease, Auray-Blais et al. (2008) identified 35 different mutations in the GLA gene, including missense (76.4%), nonsense (16.4%), frameshift (3.6%), and splice site defects (3.6%). Forty-one of the patients were being treated with enzyme replacement therapy. Although there was a wide range within each mutation group, a significant correlation existed between genotype and urinary Gb3/creatinine excretion among untreated patients, with missense mutations resulting in lower levels in general. There were also correlations between urinary Gb3/creatinine excretion and sex and between urinary Gb3/creatinine excretion and treatment. There was no correlation with age. Auray-Blais et al. (2008) developed and utilized a multiplex liquid chromatography-tandem mass spectrometry methodology that allowed for simultaneous analysis of urinary Gb3 and creatinine eluted from the same filter paper sample.
Romeo and Migeon (1970) presented evidence for a structural change in the GLA enzyme in patients with Fabry disease. The disease-associated enzymes showed slower heat inactivation and different K(m) values compared to normal.
By Southern blot ... Romeo and Migeon (1970) presented evidence for a structural change in the GLA enzyme in patients with Fabry disease. The disease-associated enzymes showed slower heat inactivation and different K(m) values compared to normal. By Southern blot analysis, Bernstein et al. (1989) found that 6 of 130 unrelated males with Fabry disease had GLA gene rearrangements. Five partial gene deletions were detected, ranging in size from 0.4 to more than 5.5 kb. Four of the 5 deletions had breakpoints in exon 2, a region containing multiple Alu repeat sequences. Kornreich et al. (1990) assessed the gene arrangements identified by Bernstein et al. (1989) to determine the possible role of Alu repetitive elements and short direct and/or inverted repeats in the generation of these germinal mutations. Although the GLA gene contains 12 Alu repetitive elements (representing about 30% of the 12-kb gene), only 1 deletion resulted from an Alu-Alu recombination. The remaining 5 rearrangements involved illegitimate recombinational events between short direct repeats of 2 to 6 bp at the deletion or duplication breakpoints. In a patient with Fabry disease, Bernstein et al. (1989) identified a mutation in the GLA gene (300644.00001). The substitution altered the enzyme's kinetic properties and stability. Eng et al. (1993) identified 18 different mutations in the GLA gene (see, e.g., 300644.0012; 300644.0013; 300644.0018-300644.0022) in patients with Fabry disease. Davies et al. (1993) found 7 mutations in the GLA gene in 9 unrelated families with the classic form of Fabry disease. Eng and Desnick (1994) reviewed and tabulated 15 GLA gene rearrangements, 3 GLA mRNA processing defects, and 31 GLA point mutations causing Fabry disease. By SSCP analysis followed by sequencing of the GLA gene, Blanch et al. (1996) identified pathogenic mutations in 9 patients with classic severe Fabry disease. In a 45-year-old man with Fabry disease who had only renal manifestations, including moderate proteinuria, Sawada et al. (1996) identified a mutation in the GLA gene (300644.0003). The mutation was inherited from his mother. The patient was unique in that he demonstrated only renal manifestations. Verovnik et al. (2004) reported the first Slovenian family with Fabry disease in which 7 males, including a set of twins, and 10 females had a GLA mutation (N272S; 300644.0062). Affected members of the family demonstrated remarkable phenotypic heterogeneity. - Modifier Genes Endothelial nitric oxide synthase (NOS3; 163729) plays a key role in the regulation of normal function of the vessel wall. Heltianu et al. (2002) found a relatively high frequency of 2 polymorphic variants of NOS3 in males with Fabry disease and suggested that in addition to mutations in the alpha-galactosidase A gene, variation in NOS3 may be significant in determining the phenotype.
The incidence of Fabry disease has been estimated at 1 in 55,000 male births. However, this figure is almost certainly a substantial underestimate of the true frequency, particularly of milder variants of the disease (Clarke, 2007).
... The incidence of Fabry disease has been estimated at 1 in 55,000 male births. However, this figure is almost certainly a substantial underestimate of the true frequency, particularly of milder variants of the disease (Clarke, 2007). Based on a newborn screening study, Spada et al. (2006) estimated that the incidence of Fabry disease may be 1 in 3,100 to 4,600 individuals.
Fabry disease should be considered in males and females with the following signs:...
DiagnosisClinical DiagnosisFabry disease should be considered in males and females with the following signs:Periodic crises of severe pain in the extremities (acroparesthesias) Vascular cutaneous lesions (angiokeratomas) Hypohidrosis Characteristic corneal and lenticular opacities Stroke Left ventricular hypertrophy Renal insufficiency of unknown etiology TestingAlpha-galactosidase A (α-Gal A) enzyme activity Males. The most efficient and reliable method for the diagnosis of Fabry disease in affected males is the demonstration of deficient α-galactosidase A (α-Gal A) enzyme activity in plasma, isolated leukocytes, and/or cultured cells. The test is a fluorometric assay and uses the substrate 4-methylumbelliferyl-α-D-galactopyranoside. Note: Both plasma and leukocyte enzyme activity should be assayed, as some pathologic mutations (e.g., p.Asn215Ser) affect intracellular trafficking or packaging/secretion of the enzyme, such that the reduction in enzyme activity in plasma is more marked than the reduction in enzyme activity in leukocytes.Males with classic Fabry disease have less than 1% α-Gal A enzyme activity. Males with atypical Fabry disease have residual enzyme activity that is greater than 1% of normal. Heterozygous females. Measurement of α-Gal A enzyme activity is unreliable for carrier detection. Although demonstration of markedly decreased α-Gal A enzyme activity in a female is diagnostic of the carrier state, some carriers have α-Gal A activity in the normal range. Molecular Genetic TestingGene. GLA is the only gene currently known to be associated with Fabry disease. Clinical testing Sequence analysis. Using complete gene sequencing, a mutation in GLA is identified in all affected males with decreased α-Gal A enzyme activity. Targeted mutation analysis. Analysis for the c.427G>C amino acid change is possible in an area where the prevalence of that mutation is high. Deletion testing. There are a variety of methods to detect exonic and whole-gene deletions in heterozygous females if: They are the only affected individual in the family available for testing and the disease-causing mutation in the family is unknown and has not been detected by sequence analysis; or They are at risk of having a family-specific mutation that is known to be an exonic deletion or whole-gene deletion. Table 1. Summary of Molecular Genetic Testing Used in Fabry DiseaseView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityAffected Males Carrier Females GLASequence analysisSequence variants 2 ~100% 3,45ClinicalTargeted mutation analysisc.427G>C100% for the targeted variantDuplication/deletion analysis 6Partial- and whole-gene deletionsSee footnote 71. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.3. Lack of amplification by PCRs prior to sequence analysis can suggest a putative deletion of one or more exons or the entire X-linked gene in a male; confirmation may require additional testing by deletion/duplication analysis.4. Includes the mutation detection frequency using deletion/duplication analysis.5. Sequence analysis of genomic DNA cannot detect deletion of one or more exons or the entire X-linked gene in a heterozygous female.6. Testing that identifies deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted array GH (gene/segment-specific) may be used. A full array GH analysis that detects deletions/duplications across the genome may also include this gene/segment. 7. Deletion/duplication analysis can be used to confirm a putative exonic/whole-gene deletion in males after failure to amplify by PCR in the sequence analysis and to identify partial- and whole-gene deletions in females.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.A number of normal allelic variants of GLA have been recorded. The most common is p.Asp313Tyr, originally reported at a frequency of 0.45% [Yasuda et al 2003a]; however, the frequency is reported to be tenfold higher by others [Gal et al 2006]. This may explain why p.Asp313Tyr has been reported in up to 5% of males with a pathogenic mutation.Testing StrategyTo confirm/establish the diagnosis in a probandFor malesDemonstration of deficient α-Gal A enzyme activity in plasma and/or isolated leukocytes is diagnostic. Note: Both plasma and leukocyte enzyme activity should be assayed, as some pathologic mutations (e.g., p.Asn215Ser) affect intracellular trafficking or packaging/secretion of the enzyme, such that the reduction in enzyme activity in plasma is more marked than the reduction in enzyme activity in leukocytes.Molecular genetic testing that identifies a GLA mutation provides additional confirmation of the diagnosis. For suspected heterozygous femalesDemonstration of markedly decreased α-Gal A enzyme activity in plasma and/or isolated leukocytes confirms the carrier state in a female. In females with α-Gal A enzyme activity in the normal range, molecular genetic testing is necessary to clarify genetic status. Note: (1) Carrier testing for at-risk females usually requires prior identification of the disease-causing mutation in the family. (2) Although carriers are heterozygotes for this X-linked disorder, they may develop significant clinical findings related to the disorder. (3) Identification of female carriers requires either (a) prior identification of the disease-causing mutation in the family or, (b) if an affected male is not available for testing, molecular genetic testing first by sequence analysis, and then, if no mutation is identified, by methods to detect gross structural abnormalities. Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutation in the family. At risk males may be diagnosed by deficient α-Gal A enzyme activityPrenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.Genetically Related (Allelic) DisordersNo phenotypes other than classic Fabry disease and its variants have been associated with mutations in GLA.
Fabry disease encompasses a spectrum of phenotypes ranging from the severe classic phenotype to atypical forms that often lack the characteristic skin lesions and acroparathesias, but have associated end-stage renal disease (ESRD), cardiac manifestations, and risk for neurologic complications such as stroke/transient ischemic attack (TIA)....
Natural HistoryFabry disease encompasses a spectrum of phenotypes ranging from the severe classic phenotype to atypical forms that often lack the characteristic skin lesions and acroparathesias, but have associated end-stage renal disease (ESRD), cardiac manifestations, and risk for neurologic complications such as stroke/transient ischemic attack (TIA).The classic phenotype is the most common; atypical forms of the disease, which present later in life, may be underdiagnosed [Sachdev et al 2002, Nakao et al 2003].The Fabry Outcome Survey (FOS) and the Fabry Registry, multicenter international initiatives designed to examine the natural history of Fabry disease and the effects of ERT, are an important source of new data on the disease [Mehta et al 2004, Eng et al 2007].Table 2. Major Manifestations in Classic and Atypical Fabry DiseaseView in own windowManifestationClassicRenal VariantCardiac VariantAge at onset4-8 yr>25 yr>40 yrAverage age of death41 yr>60 yr >60 yrAngiokeratoma++––Acroparathesias++–/+–Hypohidrosis/anhidrosis++–/+–Corneal/lenticular opacity+––HeartLVH/Ischemia 1 LVHLVH/myopathyBrainTIA 2 /stroke––KidneyESRDESRDProteinuriaResidual α-Gal A enzyme activity>1% >1% + = Present – = Absent1. LVH = Left ventricular hypertrophy2. TIA = Transient ischemic attackClassic Fabry DiseaseAffected MalesIn males with the classic form of Fabry disease, the major clinical manifestations result from the progressive lysosomal deposition of globotriaosylceramide (GL-3) in the vascular endothelium [Desnick et al 2001]. Onset of symptoms usually occurs in childhood or adolescence with periodic crises of severe pain in the extremities (acroparesthesias), the appearance of vascular cutaneous lesions (angiokeratomas), hypohidrosis, and the characteristic corneal and lenticular opacities. Although proteinuria may be detected early, renal insufficiency usually occurs in the third to fifth decade of life. Death occurs from complications of renal disease, cardiac involvement, and/or cerebrovascular disease.Angiokeratomas appear as clusters of individual punctate, dark red to blue-black angiectases in the superficial layers of the skin. The lesions may be flat or slightly raised and do not blanch with pressure. Slight hyperkeratosis is notable in larger lesions. The clusters of lesions are most dense between the umbilicus and the knees; they most commonly involve the hips, back, thighs, buttocks, penis, and scrotum, and tend to be bilaterally symmetric. However, a wide variation in the distribution pattern and density of the lesions may occur. The oral mucosa, conjunctiva, and other mucosal areas are commonly involved. Angiokeratomas are often one of the earliest manifestations of Fabry disease.The number and size of these cutaneous vascular lesions progressively increase with age. Data from 714 affected individuals (345 males, 369 females) in the Fabry Outcome Survey [Orteu et al 2007] suggest that they are present in 66% of males and 36% of females. The presence of cutaneous vascular lesions correlated with the severity of the systemic manifestations of the disease, as assessed by a modification of the Mainz severity scoring index [Whybra et al 2004].Persons with the classic phenotype with no or only a few isolated skin lesions have been reported. It should be noted that careful examination of the skin, especially the scrotum and umbilicus, may reveal the presence of isolated lesions.Pain (acroparesthesias) occurring as episodic crises of agonizing, burning pain in the distal extremities most often begin in childhood or early adolescence and signal clinical onset of the disease. These crises last from minutes to several days and are usually triggered by exercise, fatigue, emotional stress, or rapid changes in temperature and humidity. Often the pain radiates to the proximal extremities and other parts of the body. Attacks of abdominal or flank pain may simulate appendicitis or renal colic. The crises usually decrease in frequency and severity with increasing age; however, in some affected individuals, the frequency increases and the pain can be so excruciating and incapacitating that the individual may contemplate suicide.Acroparesthesias presumably result from glycosphingolipid deposition in the small vessels that supply blood to the peripheral nerves. The endothelial glycosphingolipid accumulation narrows the vascular lumen, and vessel spasms or frank infarction cause the excruciating pain.Anhidrosis, or more commonly hypohidrosis, is an early and almost constant finding. Hyperhydrosis also occurs; in the FOS registry it was seen in 12% of females and 6.4% of males [Lidove et al 2006]. Ocular involvement can include the cornea, lens, conjunctiva, and retina. A characteristic corneal opacity, termed cornea verticillata and observed only by slit-lamp microscopy, is found in affected males and most heterozygous females. The earliest corneal lesion is a diffuse haziness in the subepithelial layer. With time, the opacities appear as whorled streaks extending from a central vortex to the periphery of the cornea. The whorl-like opacities, typically inferior and cream colored, range from white to golden brown and may be very faint [Nguyen et al 2005]. In the FOS registry cornea verticillata was present in 77% of females and 73% of males undergoing detailed ophthalmic examination [Sodi et al 2007].Lenticular changes are present in approximately 30% of affected males and include a granular anterior capsular or subcapsular deposit and a unique, possibly pathognomonic, lenticular opacity (the "Fabry cataract"). The cataracts, which are best observed through a dilated pupil by slit-lamp examination using retroillumination, are whitish, spoke-like deposits of fine granular material on or near the posterior lens capsule. These lines usually radiate from the central part of the posterior cortex.The corneal and lenticular opacities do not interfere with visual acuity.Aneurysmal dilatation and tortuosity of conjuctival and retinal vessels also occur. Vessel tortuosity is observed more frequently in individuals with a higher disease severity score [Sodi et al 2007; Allen et al 2010].Cardiovascular and/or cerebrovascular disease is present in most males with the classic phenotype by middle age. The progressive vascular involvement is a major cause of morbidity and mortality, particularly after treatment of ESRD by chronic dialysis or transplantation. Mitral insufficiency may be present in childhood or adolescence. Left ventricular enlargement, valvular involvement, and conduction abnormalities are early findings.Dysrhythmias such as ST segment changes, T-wave inversion, intermittent supraventricular tachycardias, and a short PR interval may be caused by infiltration of the conduction system. Myocardial deposition may cause left ventricular hypertrophy. Echocardiography demonstrates an increased thickness of the interventricular septum and the left ventricular posterior wall [Pieroni et al 2006]. Left ventricular hypertrophy, often associated with hypertrophy of the interventricular septum and appearing similar to hypertrophic cardiomyopathy (HCM), is progressive and occurs earlier in males than females [Kampmann et al 2005].Magnetic resonance studies using gadolinium demonstrated late enhancement areas, corresponding to myocardial fibrosis and associated with decreased regional functioning as assessed by strain and strain-rate imaging [Moon et al 2003, Weidemann et al 2005]. Among 714 predominantly adult patients in FOS [Linhart et al 2007], angina, palpitations/arrhythmia, and exertional dyspnea were found in 23%-27% of males and 22%-25% of females. Hypertension, angina pectoris, myocardial ischemia and infarction, congestive heart failure, and severe mitral regurgitation are late signs. Hypertension was found in more than 50% of males and more than 40% of females in the FOS registry [Kleinert et al 2006].Cerebrovascular manifestations result primarily from multifocal small vessel involvement and may include thrombosis, transient ischemic attacks (TIA), basilar artery ischemia and aneurysm, seizures, hemiplegia, hemianesthesia, aphasia, labyrinthine disorders, or frank cerebral hemorrhage [Politei & Capizzano 2006]. Data from FOS indicate that stoke or TIA occur in approximately 13% of affected individuals overall (15% males, 11.5% females) [Ginsberg et al 2006]. Cerebrovascular manifestations are often a presenting feature of Fabry disease and may be more frequent than previously recognized. Rolfs et al [2005] reported that in Germany a GLA mutation was identified in 21 of 432 males (4.9%) and seven of 289 females (2.4%) age 18-55 years suffering cryptogenic stroke. Renal involvement. Progressive glycosphingolipid accumulation in the kidney interferes with renal function, resulting in azotemia and renal insufficiency. During childhood and adolescence, protein, casts, red cells, and birefringent lipid globules with characteristic "Maltese crosses" can be observed in the urinary sediment. Proteinuria, isothenuria, and a gradual deterioration of tubular reabsorption, secretion, and excretion occur with advancing age. Polyuria and a syndrome similar to vasopressin-resistant diabetes insipidus occasionally develop.Gradual deterioration of renal function and the development of azotemia usually occur in the third to fifth decade of life, although end-stage renal disease (ESRD) has been reported in the second decade. Death most often results from ESRD unless chronic hemodialysis or renal transplantation is undertaken. The mean age at death of males not treated for ESRD is 41 years, but occasionally an untreated male with the classic phenotype survives into the seventh decade.Other clinical features. In addition to the major clinical features described above, males and females with the classic phenotype may have gastrointestinal, auditory, pulmonary, and other manifestations. Gastrointestinal. Glycosphingolipid deposition in intestinal small vessels and in the autonomic ganglia of the bowel may cause episodic diarrhea, nausea, vomiting, bloating, cramping abdominal pain, and/or intestinal malabsorption [Hoffmann et al 2007b]. Achalasia and jejunal diverticulosis, which may lead to perforation of the small bowel, have been described. Radiographic studies may reveal thickened, edematous colonic folds, mild dilatation of the small bowel, a granular-appearing ileum, and the loss of haustral markings throughout the colon. Pulmonary. Several affected individuals have had pulmonary involvement, manifest clinically as chronic bronchitis, wheezing, or dyspnea. Primary pulmonary involvement has been reported in the absence of cardiac or renal disease. Pulmonary function studies may show an obstructive component [Magage et al 2007]. Vascular. Pitting edema of the lower extremities may be present in adulthood in the absence of hypoproteinemia, varices, or other clinically significant vascular disease. Although the pitting edema is initially reversible, progressive glycosphingolipid deposition in the lymphatic vessels and lymph nodes results in irreversible lymphedema requiring treatment with compression hosiery. Varicosities, hemorrhoids, and priapism have also been reported. Cranial nerve VIII involvement. High-frequency hearing loss, tinnitus, and dizziness have been reported [Hegemann et al 2006]. Psychological. Depression, anxiety, severe fatigue, and other psychosocial manifestations lead to decreased quality of life in many affected individuals [Cole et al 2007]. Heterozygous (Carrier) FemalesThe clinical manifestations in heterozygous females range from asymptomatic throughout a normal lifespan to as severe as affected males. Variation in clinical manifestations in heterozygous females is attributed to random X-chromosome inactivation [Deegan et al 2006].Most heterozygous females from families in which affected males have the classic phenotype have a milder clinical course and better prognosis than affected males.Mild manifestations include the characteristic cornea verticillata (70%-90%) and lenticular opacities that do not impair vision; pain/tingling in the extremities (acroparethesias) (50%-90%); angiokeratomas (10%-50%) that are usually isolated or sparse; and hypohidrosis. In addition, carriers may have chronic abdominal pain and diarrhea [Gupta et al 2005].With advancing age, carriers may develop mild to moderate enlargement of the left heart (left ventricular hypertrophy) and valvular disease. More serious manifestations include significant left ventricular hypertrophy, cardiomegaly, myocardial ischemia and infarction, cardiac arrhythmias, transient ischemia attacks, strokes, and ESRD [Shah et al 2005, Deegan et al 2006, Wilcox et al 2008].The occurrence of cerebrovascular disease including transient ischemic attacks and cerebrovascular accidents is consistent with the microvascular pathology of the disease [MacDermot et al 2001, Whybra et al 2001, Galanos et al 2002].Renal findings in heterozygotes include isothenuria, the presence of erythrocytes, leukocytes, and granular and hyaline casts in the urinary sediment, and proteinuria. According to the US and European dialysis and transplantation registries, approximately 10% of carriers develop renal failure requiring dialysis or transplantation.Excessive guilt, fatigue, occupational difficulty, suicidal ideation, and depression have been noted in heterozygotes [Sadek et al 2004].Life expectancy and cause of death. Based on data from the Fabry registry, 75 of 1422 males and 12 of 1426 females were reported to have died. The 87 deceased patients were diagnosed at a much older age than other patients in the Fabry Registry. The life expectancy of males with Fabry disease was 58.2 years, compared with 74.7 years in the general population of the United States. The life expectancy of females with Fabry disease was 75.4 years, compared with 80.0 years in the United States general population. The most common cause of death among both genders was cardiovascular disease [Waldek et al 2009]. Most patients (57%) who died of cardiovascular disease had previously received renal replacement therapy. In the Fabry outcome survey (FOS) the principal causes of death among 181 affected relatives (most of whom had died before 2001) were renal failure in males (42%) and cerebrovascular disease in females (25%) [Mehta et al 2009]. In contrast, of the 42 patients enrolled in FOS whose deaths were reported between 2001 and 2007, cardiac disease was the main cause of death in both male (34%) and female (57%) patients.Atypical Variants of Fabry DiseaseLate-onset Fabry disease with manifestations in the cardiovascular, cerebrovascular, and renal systems may be more common than previously suspected.Cardiac variant. Males with cardiac disease are asymptomatic during most of their lives and present in the sixth to eighth decade of life with left ventricular hypertrophy, mitral insufficiency and/or cardiomyopathy, and mild to moderate proteinuria with normal renal function for age. Many have been diagnosed as a result of having hypertrophic cardiomyopathy. Magnetic resonance imaging of the heart typically shows late enhancement of the posterior wall with gadolinium reflecting posterior wall fibrosis demonstrated in postmortem specimens [Moon et al 2003].Their renal pathology is limited to glycosphingolipid deposition in podocytes, which is presumably responsible for their proteinuria. They generally do not develop renal failure.Screening of males with "late-onset" hypertrophic cardiomyopathy (HCM) found that 6.3% who were diagnosed at or before age 40 and 1.4% of males who were diagnosed before age 40 had low α-Gal A enzyme activity and GLA mutations [Sachdev et al 2002]. Cardiac variants may thus be underdiagnosed among affected individuals with cardiomyopathies.The cardiac variant of Fabry disease can affect women as well as men [Colucci et al 1982, Cantor et al 1998].Renal variant. Renal variants were identified among Japanese individuals on chronic hemodialysis in whom ESRD had been misdiagnosed as chronic glomerulonephritis [Nakao et al 2003]. Of note, five of the six individuals did not have angiokeratoma, acroparesthesias, hypohidrosis, or corneal opacities, but did have moderate to severe left ventricular hypertrophy. These observations indicated that the early symptoms of classic Fabry disease may not occur in individuals with the renal variant who develop renal insufficiency, and that the renal variant may be underdiagnosed. Therefore, it is appropriate to test individuals on renal dialysis and/or undergoing renal transplantation without a primary or biopsy diagnosis for Fabry disease.
Efforts to establish genotype-phenotype correlations have been limited because each family with Fabry disease has a private mutation. ...
Genotype-Phenotype CorrelationsEfforts to establish genotype-phenotype correlations have been limited because each family with Fabry disease has a private mutation. Males with the classic phenotype have a variety of GLA mutations, including large and small gene rearrangements, splicing defects, and missense or nonsense mutations [Desnick et al 2001, Schäfer et al 2005, Human Gene Mutation Database]. Individuals with later-onset atypical variants (renal, cardiac, or cerebrovascular disease) have missense or splicing mutations that express residual α-Gal A enzyme activity [Rolfs et al 2005]. Three mutations (p.Arg112His, p.Arg301Gln, and p.Gly328Arg) have been identified in individuals with both the classic phenotype and the cardiac variant phenotype, suggesting that other modifying factors are involved in disease expression [Ashton-Prolla et al 2000]. An analysis of the FOS database showed that disease manifestations in individuals with the p.Asn215Ser mutation were less severe than those in age-matched individuals with classic Fabry disease [Schaefer et al 2005].
The pain of Fabry disease is usually associated with a low-grade fever and an elevated erythrocyte sedimentation rate (ESR); these symptoms have frequently led to the misdiagnosis of rheumatic fever, neurosis, or erythromelalgia....
Differential DiagnosisThe pain of Fabry disease is usually associated with a low-grade fever and an elevated erythrocyte sedimentation rate (ESR); these symptoms have frequently led to the misdiagnosis of rheumatic fever, neurosis, or erythromelalgia.Symptoms in individuals with Fabry disease are similar to those of other disorders including rheumatoid arthritis, juvenile arthritis, rheumatic fever, systemic lupus erythematosus (SLE), "growing pains," petechiae, Raynaud syndrome, early-onset stroke [Cabrera-Salazar et al 2005, Rolfs et al 2005] and multiple sclerosis [Callegaro & Kaimen-Maciel 2006].Males with Fabry disease may be unrecognized in cardiac clinics, where they are diagnosed with hypertrophic cardiomyopathy, and in nephrology clinics, where they are diagnosed with ESRD [Bekri et al 2005, Ichinose et al 2005, Tanaka et al 2005].Differential diagnosis of the cutaneous lesions must exclude the angiokeratoma of Fordyce spots, angiokeratoma of Mibelli, and angiokeratoma circumscriptum, none of which has the typical histologic or ultrastructural lysosomal storage pathology of the Fabry lesion. The angiokeratoma of Fordyce spots are similar in appearance to those of Fabry disease but are limited to the scrotum and usually appear after age 30 years. The angiokeratoma of Mibelli are warty lesions on the extensor surfaces of extremities in young adults and are associated with erythematosus subcutaneous swellings. Angiokeratoma circumscriptum or naeviformus can occur anywhere on the body, are clinically and histologically similar to those of Fordyce, and are not associated with chilblains (erythematous subcutaneous swellings). Angiokeratoma, in clinical appearance and distribution reportedly similar to or indistinguishable from the cutaneous lesions seen in individuals with Fabry disease, have been described in individuals with other lysosomal storage diseases, including fucosidosis, sialidosis (α-neuraminidase deficiency with or without β-galactosidase deficiency), adult-type β-galactosidase deficiency, aspartylglucosaminuria, adult-onset α-galactosidase B deficiency, β-mannosidase deficiency, and a lysosomal disorder with intellectual disability and some features of the mucopolysaccharidoses [Desnick et al 2001].Note to clinicians: For a patient-specific ‘simultaneous consult’ related to Fabry disease, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).Affected malesHeterozygous females
To establish the extent of disease in an individual diagnosed with Fabry disease, the following evaluations are recommended:...
ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with Fabry disease, the following evaluations are recommended:Careful history for evidence of acroparesthesias and hypohidrosis or other manifestations of the disorder Renal function studies Cardiac evaluation, including echocardiography Examination of the skin for angiokeratomas Formal audiologic assessment Ophthalmologic evaluation Neurological assessmentTreatment of ManifestationsAcroparesthesias Diphenylhydantoin. The severe pain of such episodes in affected males and carriers often responds to low-maintenance doses of diphenylhydantoin by reducing the frequency and severity of the periodic crises of excruciating pain and constant discomfort. Carbamazepine has similar effects. The combination of the two drugs may also significantly reduce the frequency and severity of the pain. Potential side effects are gingival hypertrophy with diphenylhydantoin and dose-related autonomic complications with carbamazepine, including urinary retention, nausea, vomiting, and ileus. Gabapentin has been demonstrated to improve pain [Ries et al 2003]. Renal disease. Renal insufficiency is the most frequent and serious late complication in males with the classic phenotype; therefore, ACE inhibitors should be used in those with evidence of renal involvement, especially to reduce proteinuria. Chronic hemodialysis and/or renal transplantation have become lifesaving procedures. The engrafted kidney remains histologically free of glycosphingolipid deposition because the normal α-Gal A enzyme activity in the allograft catabolizes endogenous renal glycosphingolipid substrates. Therefore, successful renal transplantation corrects renal function.Reviews of the registries of the European Renal Association-European Dialysis and Transplantation Association and the United States Renal Data System support excellent outcomes for renal transplantation in individuals with Fabry disease. For example, during the ten-year period from 1988 to 1998, 93 individuals who underwent renal transplantation were reported to the US registry. Compared to a matched control group, recipients with Fabry disease had equivalent five-year life survival (82% vs 83%) and graft survival (67% vs 75%), respectively.Note: (1) Immune function in males with Fabry disease is similar to that in other individuals with uremia, obviating any immunologic contraindication to transplantation in this disease. Autoimmune conditions have, however, been reported to occur at an increased frequency in Fabry disease [Martinez et al 2007]. (2) Transplantation of kidneys from carriers for Fabry disease should be avoided, as the organs may already contain significant substrate deposition; all related potential donors must be evaluated to exclude affected males and carrier females.Prevention of Primary Manifestations Enzyme replacement therapy (ERT). The two ERTS using recombinant or gene-activated human α-Gal A enzyme that have been evaluated in clinical trials are Fabrazyme® (algalsidase beta; Genzyme Corp) and ReplagalTM (algalsidase alpha; Shire Genetic Therapies, UK). Both were approved in 2001 by the European Agency for Evaluation of Medical Products; only Fabrazyme® was approved by the FDA for use in the US. The following is a summary of some of the clinical trials for each drug:In a single-center, double-blind, placebo-controlled Phase II trial of ReplagalTM, 26 males selected for the presence of pain received either 0.2 mg/kg of enzyme or placebo every two weeks for a total of 12 doses. The primary efficacy end point was reduction of pain. Severity of neuropathic pain improved in the 14 treated with enzyme and changed little in the 12 who received the placebo, a statistically significant effect of treatment of pain [Schiffmann et al 2001]. The individuals treated with enzyme had an approximately 50% reduction in plasma GL-3 concentration, a significant improvement in cardiac conduction, a significant increase in body weight, and some improvement in certain tests of renal function. In a European study of 15 severely affected female heterozygotes treated for up to 55 weeks, ERT was safe and well tolerated [Baehner et al 2003]. A Phase III clinical trial of Fabrazyme®, a multinational, double-blind, randomized, placebo-controlled study, demonstrated that individuals who received Fabrazyme® (1 mg/kg every two weeks for a total of 11 doses) cleared GL-3 from the endothelial cells of the kidney, heart, and skin, whereas those treated with placebo did not [Eng et al 2001, Thurberg et al 2002]. In the double-blind study, the primary efficacy end point was the clearance of GL-3 from the interstitial capillary endothelial cells of the kidney. At the end of the double-blind study, 20 of the 29 (69%) individuals in the Fabrazyme®-treated group were free of microvascular endothelial deposits of GL-3 as compared with none of the 29 individuals in the placebo group (P<0.001). Individuals in the Fabrazyme®-treated group also had decreased microvascular endothelial deposits of GL-3 in the skin (P<0.001) and heart (P<0.001) compared with those receiving the placebo. In individuals treated with enzyme, plasma levels of GL-3 decreased into normal range. In conjunction with the accelerated approval process for Fabrazyme®, the FDA required a Phase IV study to evaluate the direct clinical benefit of the drug after marketing approval. This double-blind, placebo-controlled trial involving 76 individuals with Fabry disease with mild to moderate renal insufficiency began in early 2001. The risk of major clinical events (a combination of death, myocardial infarction, stroke, development of ESRD, or a 33% increase in serum creatinine concentration) was reduced 53% by agalsidase beta after adjustment for baseline proteinuria (P=0.06) [Banikazemi et al 2007]. Experience with Fabrazyme® in Europe indicated that it stabilized deteriorating renal function [De Schoenmakere et al 2003] and improved cardiac function [Waldek 2003, Weidemann et al 2003]. Improvement in the function of C-, Aδ-, and Aβ-nerve fibers in the neuropathy of Fabry disease also improved [Hilz et al 2004]. A retrospective survey of 17 individuals showed decreased pain severity and occurrence and improved heat tolerance and psychological well-being [Guffon & Fouilhoux 2004]. A study of three individuals with Fabry disease with kidney transplantation showed decreased plasma GL-3 concentrations, decreased extremity pain, and improved cardiac function, indicating that ERT is safe and effective against extrarenal manifestations of Fabry disease [Mignani et al 2004]. Also, ERT can be carried out during hemodialysis because the enzyme is not lost in the dialysate. Treatment with agalsidase alfa appears capable of stabilizing hearing loss [Hajioff et al 2003, Hajioff et al 2006]. Peripheral nerve function and sweating improved [Schiffmann et al 2003]. ERT with agalsidase alfa significantly improved quality of life in females [Deegan et al 2006] and in both males and females [Hoffmann et al 2005]. Data from FOS suggest that agalsidase alfa may slow deterioration of renal and cardiac disease, reduce pain, and improve quality of life [Beck et al 2004, Schwarting et al 2006, Hoffmann et al 2007a]. The enzyme is safe in children [Ramaswami et al 2006]. In persons with advanced renal disease, weekly administration of 0.2 mg/kg agalsidase alfa may be associated with a slower decline in renal function [Schiffmann et al 2007]. The addition of ACE inhibitors and ARB blockade, in association with agalsidase beta, helps slow decline of renal function [Tahir et al 2007]. A small comparative study of agalsidase alfa or beta at a dose of 0.2 mg/kg showed no difference in reduction of left ventricular mass or other disease parameters after 12 or 24 months of treatment [Vedder et al 2007]. Antibody formation has been reported with both agalsidase alfa and beta in males, but not females [Linthorst et al 2005]; however, the impact of this on the overall efficacy of treatment is currently unknown. A panel of physician experts have recommended that ERT be initiated as early as possible in all males with Fabry disease, including children and those with ESRD undergoing dialysis and renal transplantation, and in female carriers with significant disease [Desnick et al 2003, Eng et al 2006] because all are at high risk for cardiac, cerebrovascular, and neurologic complications, such as transient ischemic attacks and strokes.Prevention of Secondary ComplicationsThe prophylaxis of renovascular disease, ischemic heart disease, and cerebrovascular disease in persons with Fabry disease is the same as for the general population. Proteinuria/albuminemia should be minimized with ACE/ARB [Tahir et al 2007]; blood pressure control optimized; and cholesterol normalized. Aspirin and other anti-platelet agents such as clopidogrel may be recommended for the prophylaxis of stroke. Although evidence as to the effect on long term outcomes is lacking,use of aspirin and lipid-lowering agents and optimal blood pressure control are recommended in persons with symptoms of cardiac ischemia [Eng et al 2006]. The role of ERT in the long-term prophylaxis of renal, cardiac, and CNS manifestations is unproven; however, on the basis of stabilization of organ function in persons with more advanced disease, some have suggested the initiation of ERT in early disease stages: at first sign of disease manifestations in boys; at age 12-13 years in asymptomatic boys; and at the time of diagnosis in adult males [Eng et al 2006].SurveillanceThe following are appropriate:Annual or more frequent renal function studies Annual cardiology evaluation Annual hearing evaluation Agents/Circumstances to AvoidThe obstructive lung disease, which has been documented in older hemizygous males and heterozygous females, is more severe in smokers; therefore, affected individuals should be discouraged from smoking.Amiodarone has been reported to induce cellular and biochemical changes resulting in a phenocopy in particular of the keratopathy of Fabry disease [Whitley et al 1983]. Given potential effects on cellular levels of alpha galactosidase A enzyme activity, it has been contraindicated in persons with Fabry disease. However, little evidence of a detrimental effect in this specific group exists and the relative benefit in patients with cardiac arrhythmia should be considered.Evaluation of Relatives at RiskGiven the availability of ERT, early identification of affected relatives is warranted by molecular genetic testing if the disease-causing mutation has been identified in the family. See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationGene replacement therapy has been investigated in the mouse model of Fabry disease [Ziegler et al 1999, Ziegler et al 2002, Ziegler et al 2004]; no human trials have been undertaken to date. Chaperone therapy, a novel approach, uses small molecules designed to enhance the residual enzyme activity by protecting the mutant enzyme from misfolding and degradation in the cell [Desnick & Schuchman 2002]. A report of chaperone therapy in a male with the cardiac variant demonstrated the "proof of concept" for this therapeutic strategy for Fabry disease [Frustaci et al 2001]. Phase I trials have demonstrated elevation of plasma alpha galactosidase levels in healthy volunteers [Fan et al 1999, Ishii et al 2004]. Phase II trials are now in progress in males and females with Fabry disease with a pharmacologic chaperone (1-deoxygalactonorijimycin; DGJ; AmigalTM; Amicus Therapeutics, NJ, USA). DGJ has been demonstrated to enhance trafficking of mutant alpha-galactosidase A to lysosomes of fibroblasts derived from persons with Fabry disease and increase enzyme activity while reducing GL-3 substrate in tissues of a transgenic/knockout animal model of Fabry disease.Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.OtherDespite biochemical rationale for the potential use of substrate reduction therapy in Fabry disease, this approach has not thus far proven to have clinical merit.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Fabry Disease: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDGLAXq22.1Alpha-galactosidase AGLA @ LOVD CCHMC - Human Genetics Mutation DatabaseGLAData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Fabry Disease (View All in OMIM) View in own window 300644GALACTOSIDASE, ALPHA; GLA 301500FABRY DISEASENormal allelic variants. GLA spans approximately 13 kb of gDNA and contains seven exons; the cDNA is 1290 bases and encodes a polypeptide of 429 amino acids including a 31-amino acid signal peptide. p.Asp313Tyr, a common exon 6 variant with decreased activity in vitro and reduced activity at neutral pH resulting in low plasma α-Gal A activity, has been identified in 0.45% of normal individuals (n = 800 alleles). Expression of p.Asp313Tyr in COS-7 cells resulted in approximately 60% of wild-type enzymatic activity and showed normal lysosomal localization [Froissart et al 2003, Yasuda et al 2003b]. Thus, p.Asp313Tyr is a variant that does not cause Fabry disease. Pathologic allelic variants. In classic Fabry disease, affected males have a variety of pathologic allelic variants, including missense and nonsense mutations, large and small gene rearrangements, and splicing defects. More than 300 mutations have been identified and most are family specific, occurring only in single pedigrees [Desnick et al 2001, Germain et al 2002, Shabbeer et al 2002, Rodriguez-Mari et al 2003, Stenson et al 2003, Schäfer et al 2005]. However, mutations at CpG dinucleotides have been found in unrelated families of different ethnic or geographic backgrounds. Haplotype analysis of mutant alleles that occurred in two or more families reveals that those with rare alleles are probably related, whereas those with mutations involving CpG dinucleotide "hot spots" are not [Ashton-Prolla et al 2000]. Very few de novo mutations have been detected; however, data are not available on the frequency of germline mosaicism. In the cardiac variant of Fabry disease, all individuals to date have missense or splicing mutations that expressed residual α-Gal A activity, including p.Ile91Thr, p.Arg112His, p.Phe113Leu, p.Asn215Ser, p.Met296Ile, p.Arg301Gln, and p.Gly328Arg. (Of note, the p.Asn215Ser mutation was found in several unrelated individuals with the cardiac variant.) All renal variants identified to date have been associated with missense mutations [Nakao et al 2003]. Three mutations (p.Arg112His, p.Arg301Gln, and p.Gly328Arg) have been identified in individuals with the classic phenotype and the cardiac variant phenotype, suggesting that other modifying factors are involved in disease expression [Ashton-Prolla et al 2000]. (For more information, see Table A.) Table 3. Selected GLA Allelic VariantsView in own windowType of VariantDNA Nucleotide Change Protein Amino Acid ChangeReference SequencesNormalc.937G>Tp.Asp313TyrNM_000169.2 NP_000160.1Pathologicc.272T>Cp.Ile91Thrc.335G>Ap.Arg112His 1c.337T>Cp.Phe113Leuc.427G>C p.Ala143Proc.644A>Gp.Asn215Serc.888G>Ap.Met296Ilec.902G>Ap.Arg301Gln 1c.982G>Ap.Gly328Arg 1See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org). 1. See Genotype/Phenotype CorrelationsNormal gene product. Alpha-galactosidase A (a/pha-Gal A) is a lysosomal exoglycohydrolase. The mature α-Gal A enzyme polypeptide is 398 amino acids and contains three functional N-glycosylation sites. The active enzyme is a homodimer of approximately 101 kd. Abnormal gene product. GLA mutations result in mRNA instability and/or severely truncated α-Gal A or an enzyme with markedly decreased activity.