Fabry Disease

A number sign (#) is used with this entry because Fabry disease is caused by mutations in the GLA gene (300644), encoding alpha-galactosidase A, on chromosome Xq22. A cardiac variant of Fabry disease is also caused by mutation in the GLA gene.

Description

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 Fabry disease was previously considered to be 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.

Clinical Features

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.

Other Features

Cable et al. (1982) reported impaired autonomic function in 10 patients with Fabry disease. All had decreased sweating and about half had impaired pupillary constriction and decreased saliva and tear formation. Older patients showed disordered intestinal mobility. Friedman et al. (1984) reported a patient with Fabry disease who had jejunal diverticulosis complicated by perforation and abscess formation. Microscopic examination showed glycolipid deposition in the neurons and nerve fibers of the intestinal myenteric plexus and smooth muscle. Friedman et al. (1984) concluded that uncoordinated smooth muscle activity resulting from Fabry disease caused mucosal protrusion through the smooth muscle.

Rosenberg et al. (1980) pointed out that deposition of sphingolipid in epithelial cells of the respiratory tract leads to chronic obstruction of airflow; the effect was especially apparent in smokers.

Among 25 male patients with Fabry disease, Brown et al. (1997) reported dyspnea in 36% and cough and/or wheezing in 24%. Symptoms were similar in smokers and nonsmokers. Nine (36%) had airway obstruction on spirometry; this finding was associated with age of more than 26 years and with dyspnea or wheezing, but only weakly associated with smoking. Five of 8 patients responded to bronchodilators, but all 10 methylcholine challenges were negative. Chest radiographs showed normal lung fields in 24 patients and streaky bibasilar densities in 1. Specific GLA mutations were identified in 17 patients; all 3 patients with frameshift mutations and both subjects with an N264V mutation (300644.0021) had obstructive impairment. Brown et al. (1997) concluded that airway obstruction occurs commonly in patients with Fabry disease regardless of smoking history, and that it increases with age. The presence of obstruction may be associated with certain mutations and most likely results from fixed narrowing of the airways by accumulated glycosphingolipid.

Germain et al. (2002) concluded that progressive hearing loss and sudden deafness are frequent findings in Fabry disease. Abnormal hearing was found in 12 (54.5%) of 22 hemizygous males aged 19 to 64 years: progressive hearing loss in 5 and sudden deafness in 7. Hearing loss on high-tone frequencies was found in 7 of the 10 remaining patients without clinical impairment, despite a young age. The incidence of hearing loss appeared significantly increased in patients with kidney failure or cardiovascular lesions, whereas there was no correlation with left ventricular hypertrophy. Tinnitus aurium was found in 6 patients (27%).

Germain et al. (2005) prospectively investigated bone involvement in 23 consecutive hemizygous male patients with Fabry disease using dual energy x-ray absorptiometry and found that 20 (87%) had either osteopenia or osteoporosis. The authors stated that this was the first study demonstrating that Fabry disease is associated with an increased risk of decreased bone mineral density.

Kaneski et al. (2006) observed significantly increased serum myeloperoxidase (MPO; 606989) levels in 73 male patients with Fabry disease compared to controls. Follow-up for a mean of 6 years showed that increased serum MPO was associated with increased risk for vascular events. Heterozygous female Fabry carriers also had increased MPO levels compared to controls, but the difference was not statistically significant. Long-term enzyme replacement therapy did not reduce MPO levels or eliminate the risk of vasculopathic events. Kaneski et al. (2006) hypothesized that the increased MPO in Fabry disease was produced by neutrophils in response to reactive oxygen species.

To investigate the function and morphology of the endocrine glands in patients with Fabry disease, Faggiano et al. (2006) evaluated the thyroid, gonadal, adrenal, and growth hormone/insulin-like growth factor-1 (139250/147440) axes in 18 Fabry disease patients and 18 sex- and age-matched healthy subjects. Ten of the 18 patients received enzyme replacement therapy. Fabry disease patients had higher baseline thyroid-stimulating hormone (TSH; see 188540) levels than controls (P less than 0.01). Three subjects were diagnosed with an early stage of subclinical primary hypothyroidism associated with negative antithyroid antibodies. A history of menstrual abnormalities, miscarriage, or assisted delivery was found in 89% of women with Fabry disease. Asthenozoospermia, oligozoospermia, or both were found in all men with Fabry disease through seminal fluid analysis. Fabry disease patients had significantly higher circulating ACTH and lower cortisol levels than controls (P less than 0.05). In patients under enzyme replacement therapy, a suboptimal cortisol response to the 250-microgram ACTH test was found in 10%, and the ACTH-stimulated cortisol peak was significantly correlated to the health status profile (P less than 0.05). Faggiano et al. (2006) concluded that a variety of latent endocrine dysfunctions, including life-threatening conditions (e.g., adrenal insufficiency), occur in patients with Fabry disease. Endocrine dysfunctions are also present in patients already receiving enzyme replacement therapy and are in part related to their persistent poor quality of life.

Using a personality inventory questionnaire to evaluate the psychologic profile of 28 adult patients with Fabry disease, Crosbie et al. (2009) found that the patients had significantly higher (abnormal) scores on several scales, including hypochondriasis, depression, and hysteria, compared to the general population and compared to patients with chronic heart disease. However, the psychologic profiles were similar to patients with chronic pain. Fabry patients reported high levels of pain, difficulty tolerating extreme temperatures, feeling tired or weak, and gastrointestinal problems. Fabry patients appeared preoccupied with health problems, resulting in isolation, unhappiness, worry, despair, and emotional turmoil, indicating the serious nature of this chronic debilitating disease.

Biochemical Features

Aerts et al. (2008) found that patients with Fabry disease had dramatically increased plasma deacylated Gb3 (globotriaosylsphingosine, or lyso-Gb3). The authors noted that lyso-Gb3 is highly hydrophilic, which may explain why it had been overlooked for many years. Plasma measurement of several Fabry patients, including a large Dutch family, showed marked increases of plasma lyso-Gb3 in hemizygotes at a young age. Heterozygous females carriers had mild increases of lyso-Gb3. Further studies showed that Gb3 at these concentrations promoted Gb3 storage, induced proliferation of smooth muscle cells, and inhibited GLA activity. Enzyme replacement therapy resulted in reduced, but not normalized, plasma levels of lyso-Gb3. Aerts et al. (2008) postulated that high levels of lyso-Gb3 may provide explanations for poorly understood phenomena in Fabry disease, including proliferation of smooth vascular endothelial cells, manifestations in heterozygous females, or extralysosomal accumulation of Gb3.

In 73 men with Fabry disease followed before and after enzyme replacement therapy, Schiffmann et al. (2013) found that changes in globotriaosylceramide concentrations did not appear to be useful biomarkers for prediction of Fabry disease-related changes in estimated glomerular filtration rate or left ventricular mass index.

Diagnosis

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.

Clinical Management

Eng et al. (2006) published guidelines for the evaluation and management of multiorgan system involvement in patients with Fabry disease.

Wang et al. (2011) described the ACMG standards and guidelines for the diagnostic confirmation and management of presymptomatic individuals with lysosomal storage diseases.

Renal Transplantation

Clement et al. (1982) reported that successful renal transplantation in Fabry disease not only corrected the anemia but also produced a marked improvement in other clinical manifestations of the disease. Bannwart (1982) described a postmortem examination 12 years after transplantation; no histologic recurrence of Fabry disease in the kidney graft was found by light or electron microscopy. In contrast, Faraggiana et al. (1981) examined the kidney of a patient who died 6 months following transplantation and found widespread recurrence of the disease in the graft. In that case, there was evidence of a circulating inhibitor of galactosidase A activity.

Friedlaender et al. (1987) presented renal biopsy data on a patient with Fabry disease before and 8 years after successful renal transplantation. The graft maintained normal function and graft histology showed no abnormalities. The patient had been able to return to work and his severe symptoms of acroparesthesia had been cured.

Enzyme Replacement Therapy

Mapes et al. (1970) reported one of the first enzyme replacement strategies in Fabry disease. Two patients demonstrated a decline in the plasma level of galactosylgalactosylglucosylceramide when normal plasma was infused to provide active enzyme.

Fan et al. (1999) proposed a molecular therapeutic strategy for Fabry disease in which competitive inhibitors are administered as 'chemical chaperones' at subinhibitory intracellular concentrations to enhance residual enzyme activity in Fabry disease. Some mutant alpha-Gal A enzymes have shown kinetic properties similar to those of wildtype, but are significantly less stable, especially in conditions of neutral pH. The biosynthetic processing was delayed in cultured fibroblasts of a Fabry disease patient (Lemansky et al., 1987), and the mutant protein formed an aggregate in endoplasmic reticulum (Ishii et al., 1996), indicating that the enzyme deficiency in some mutants is mainly caused by abortive exit from the endoplasmic reticulum, leading to excessive degradation of the enzyme. Fan et al. (1999) and Asano et al. (2000) reported that 1-deoxygalactonojirimycin (DGJ), a potent competitive inhibitor of alpha-Gal A, effectively enhanced enzyme activity in Fabry disease lymphoblasts when administered in concentrations lower than those usually required for intracellular inhibition of the enzyme. DGJ seemed to accelerate transport and maturation of the mutant enzyme. Oral administration of DGJ to transgenic mice overexpressing a mutant alpha-Gal A substantially elevated enzyme activity in some organs.

Schiffmann et al. (2000) studied the safety and pharmacokinetics of intravenously administered alpha-galactosidase A produced by transfection of human skin fibroblasts in patients with Fabry disease. Infusions were well tolerated in all patients. Immunohistochemical staining of liver tissue approximately 2 days after enzyme infusion identified alpha-galactosidase A in several cell types, suggesting diffuse uptake via the mannose 6-phosphate receptor (M6PR; 154540). The tissue half-life in the liver was greater than 24 hours. The degree of substrate reduction as potentially clinically significant was observed from studies of glycosphingolipid globotriaosylceramide (also referred to as ceramidetrihexoside) levels in the patients after a single dose of alpha-galactosidase A. Brady and Schiffmann (2000) reviewed the clinical features of Fabry disease and recent advances in its therapy. They stated that their double-blind, placebo-controlled trial of intravenous infusions of alpha-galactosidase A in patients with Fabry disease demonstrated the safety and efficacy of this treatment. Eng et al. (2001) reported the results of a clinical trial of enzyme replacement in Fabry disease indicating overall safety and subjective and objective evidence of improvement.

Two differently produced enzyme preparations have independently been examined in clinical investigations for the treatment of Fabry disease: one produced by Chinese hamster ovary (CHO) cells with classic recombinant technology (agalsidase-beta, Fabrazyme), and the other produced by cultured human skin fibroblasts with an activated promoter of the alpha-Gal A gene (agalsidase-alpha, Replagal). With both preparations, promising lipid substrate reductions in tissue biopsies have been observed (Eng et al., 2001; Pastores and Thadhani, 2001; Schiffmann et al., 2001). Although it had been suggested that alpha-Gal A mRNA undergoes editing, which might result in coproduction of an edited protein with a phe396-to-tyr conversion that might have a relevant physiologic function (Novo et al., 1995), Blom et al. (2003) found no indication for the existence of editing at the protein or RNA levels in either recombinant GLA enzyme.

Waldek (2003) suggested that duration of the PR interval may be a useful marker of both the severity of cardiac disease and the response to treatment in patients with Fabry disease. In a patient who had a favorable response to enzyme replacement therapy, the PR interval and cardiac globotriaosylceramide level were restored to normal values, with an improvement in cardiac function shown by the increase in the left ventricular ejection fraction. The rapid increase in the PR interval coincided with a dramatic decline in the cardiac glycosphingolipid level.

Wilcox et al. (2004) reported that enzyme replacement therapy for 30 to 36 months with agalsidase-beta resulted in continuously decreased plasma globotriaosylceramide levels, sustained endothelial Gb3 clearance, stable kidney function, and a favorable safety profile.

Using clinical, electrocardiographic, and echocardiographic evaluation, Spinelli et al. (2004) studied 9 patients with Fabry cardiomyopathy before and after 6 and 12 months of treatment with agalsidase-beta. At 12 months, interventricular septal thickness and left ventricular mass had decreased significantly (p less than 0.01 for both), as had the difference in duration between the pulmonary vein flow velocity wave and the mitral wave at atrial systole (p less than 0.01). Spinelli et al. (2004) suggested that enzyme replacement therapy in patients with Fabry cardiomyopathy is able to reduce the left ventricular mass and ameliorate its stiffness. (Pisani (2005) stated that the p values were incorrect in the abstract but correct in the figures of the article of Spinelli et al. (2004).)

Tajima et al. (2009) designed and produced a modified alpha-N-acetylgalactosaminidase (NAGA; 104170) with alpha-galactosidase A (GLA)-like substrate specificity in Chinese hamster ovary cells. The enzyme acquired the ability to catalyze the degradation of 4-methylumbelliferyl-alpha-D-galactopyranoside, an artificial substrate of GLA, but not for a NAGA substrate. It showed stability in plasma and had mannose 6-phosphate residues for incorporation into cells. There was no immunologic crossreactivity between the modified NAGA and GLA, and the modified NAGA did not react to serum from a patient with Fabry disease treated with a recombinant GLA. In cultured fibroblasts from a patient with Fabry disease, the modified enzyme cleaved accumulated globotriaosylceramide (Gb3). Intravenous injection into Fabry mice prevented Gb3 storage in the liver, kidneys, and heart, and improved pathologic changes in these organs. Tajima et al. (2009) concluded that this modified NAGA could be a highly promising safe enzyme for treatment of Fabry disease.

Germain et al. (2013) evaluated the progression of left ventricular hypertrophy in untreated men with Fabry disease and compared them with treated men. They analyzed longitudinal Fabry Registry data from 115 men treated with 1 mg/kg agalsidase-beta for 2 weeks and 48 untreated men. Measurements included baseline left ventricular mass and at least 1 additional left ventricular mass assessment over at least 2 years. Patients were grouped into quartiles, based on left ventricular mass slopes. Multivariate logistic regression analyses identified factors associated with left ventricular hypertrophy progression. For men in whom treatment was initiated at the age of 18 to less than 30 years (n = 31), mean left ventricular mass slope was -3.6 g/year, compared with +9.5 g/year in untreated men of that age (n = 15) (p less than 0.0001). Untreated men had a 3.4-fold higher risk of having faster increases in left ventricular mass compared with treated men (odds ratio 3.43; 95% confidence interval 1.05-11.22; p = 0.0415). A baseline age of 40 or more years was also associated with left ventricular hypertrophy progression (odds ratio 5.03; 95% confidence interval 1.03-24.49; p = 0.0457) compared with men younger than 30 years. Germain et al. (2013) concluded that agalsidase-beta treatment for 2 or more years may improve or stabilize left ventricular mass in men with Fabry disease.

Germain et al. (2015) reported a 10-year follow-up of 52 Fabry patients treated with agalsidase. The mean age of patients at treatment initiation was 30 years; 11 patients were over age 40. Twenty patients had high renal involvement and 32 had low renal involvement at the onset of treatment. Most patients (81%) did not have any severe clinical events during the interval, and 94% were alive at the end of the study. Ten patients reported a total of 16 adverse events, most frequently stroke, followed by a severe renal event (dialysis, transplant) and cardiac events. Renal disease progressed in almost all patients despite treatment but was slower and less severe in those treated at a younger age and those who had low kidney involvement at the outset. The mean left ventricular posterior wall thickness and interventricular septum thickness remained unchanged and normal among treated patients. The findings indicated that treatment with agalsidase is effective in Fabry disease, and that early treatment is most beneficial.

Gene Therapy

Qin et al. (2001) used a novel bicistronic retroviral vector that engineers expression of both the therapeutic GLA gene and the human IL2R-alpha chain gene (CD25; 147730) as a selectable marker. Coexpression of IL2R-alpha allowed selective immunoenrichment, preselection, of a variety of transduced human and murine cells, resulting in enhanced intracellular and secreted activities of the alpha-Gal A enzyme. The results suggested that a CD25-based preselection strategy may enhance the clinical utility of ex vivo hematopoietic stem/progenitor cell gene therapy in Fabry disease and other disorders.

Migalastat Therapy

Hughes et al. (2017) performed an 18-month randomized active-controlled study to access the effects of migalastat on renal function in patients with Fabry disease previously treated with enzyme replacement therapy (ERT). Effects on heart, disease substrate, patient-reported outcomes, and safety were also assessed. Fifty-seven adults (56% female) receiving ERT (88% with multiorgan disease) were randomized (1.5:1), based on a preliminary cell-based assay of responsiveness to migalastat, to receive 18 months open-label migalastat or remain on ERT. Migalastat and ERT had similar effects on renal function. Left ventricular mass index decreased significantly with migalastat treatment (-6.6 g/m(2), range -11.0 to -2.2); there was no significant change with ERT. Predefined renal, cardiac, or cerebrovascular events occurred in 29% and 44% of patients in the migalastat and ERT groups, respectively. Plasma globotriaosylsphingosine remained low and stable following the switch from ERT to migalastat. Patient-reported outcomes were comparable between groups. Migalastat was generally safe and well tolerated.

Mapping

Opitz et al. (1965) reported linkage between Fabry disease and the X chromosome. Johnston et al. (1969) estimated the recombination fraction of Fabry versus Xg (314700) to be 0.24 (95% probability limits, 8-49.8%) and of angiokeratoma versus deutan (303800) to be 0.17 (95% probability limits, 1-50%). Johnston and Sanger (1981) reanalyzed all data on Xg and Fabry linkage and obtained negative lod scores at all recombination rates.

MacDermot et al. (1987) found close linkage between Fabry disease and 3 DNA markers on the X chromosome: DXS87, DXS88, and DXS17, which gave maximum lod scores of 6.4, 6.4, and 5.8, respectively, at theta = 0.00. DXYS1 was not linked.

Molecular Genetics

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 (300644.0001). 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