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Fabry's Disease

Historical Overview

In 1898, two dermatologists, Johann Fabry in Dortmund, Germany and William Anderson in London, England, independently described the first patients with the disorder now known as Fabry disease. Forty years later, it was recognized that the disease resulted from abnormal deposits of a particular fatty substance (known as globotriaosylceramide) in blood vessel walls throughout the body. In the 1960's, the primary defect was identified as the inherited deficiency of the enzyme, a-galactosidase A, which is normally responsible for the breakdown of globotriaosylceramide. The gene for this enzyme was isolated and characterized in 1986 at Mount Sinai, permitting improved diagnosis, especially of female carriers, and the capability to produce large amounts of the normal enzyme for trials of enzyme replacement therapy.

Lymphatic involvement:

Fabry's Disease or syndrome is a condition with possible lymphatic dysplasia involved and thus will present with lymphedema.

The lymphedema treatment program would include: Manual lymphatic drainage; compression wraps or compression bandages (using short stretch bandages), compression garments, compression sleeves.

Pat O'Connor

June 23, 2008


Abstracts and Articles relating to lymphedema and Fabry Disease:


Fabry's disease with familial lymphedema of the lower limbs. Case report and family study.

Eur Neurol. 1979

Gemignani F, Pietrini V, Tagliavini F, Lechi A, Neri TM, Asinari A, Savi M.

The case of a 49-year-old man with Fabry's disease (FD), confirmed by histopathological findings of kidney and skin biopsies and enzymatic studies, is reported. Clinical symptoms mainly consisted in severe neurological involvement, and in conspicuous lymphedema of the lower limbs. Two decreased brothers of the patient were also affected with symptons strongly suggesting FD, as well as the lymphedema of the lower limbs. On the basis of these data, the association of FD with familial lymphedema of the lower limbs is discussed: a lipid accumulation in the lymphatic as well as the blood vessel wall is proposed as a possible explanation; the hypothesis of an inborn error in the development of the lymphatic system, controlled by a gene closedly associated with the FD gene on the same chromosome can also be advanced.



Severe lymphatic microangiopathy in Fabry disease.

Lymphat Res Biol. 2003

Amann-Vesti BR, Gitzelmann G, Widmer U, Bosshard NU, Steinmann B, Koppensteiner R.

University Hospital of Zurich, Zurich, Switzerland.

BACKGROUND: Lymphedema has been described in a few cases of Fabry disease. The etiology of lymphedema in Fabry disease is unknown. The aim of the study was to evaluate morphology and function of lymphatic microvessels in this disease. 

METHODS AND RESULTS: In five male patients with Fabry disease, the initial lymphatic microvessels of the skin were studied in vivo, using a nearly atraumatic technique of fluorescence microlymphography and measurement of lymph capillary pressure. In addition, five female patients heterozygous for Fabry disease and 12 healthy controls were studied. The maximum spread of the fluorescent macromolecular dye into the network of superficial skin lymphatics was increased in the three male patients presenting with lymphedema (25, 26, and 45 mm, respectively). In the two male patients without swollen legs, the maximum spread of the dye was 3 and 7 mm, respectively, and in the female patients 8.8 mm (range, 4-17 mm), whereas in the healthy controls it reached only 4.3 mm (range, 1-7 mm). Fragmentation of the microlymphatic network was found in all patients, but not in controls. In controls, the diameter of the microvessels varied in a very narrow range (45-75 microm); in patients, the range was 15-150 microm. In patients with lymphedema, microlymphatic hypertension was present. 

CONCLUSION: In patients with Fabry disease severe structural and functional changes of the initial lymphatics of the skin are present.



Atypical symptoms of Fabry's disease: sudden bilateral deafness, lymphedema and Lown-Ganong-Levine syndrome

Pol Arch Med Wewn. 2002 Nov

Undas A, Ryś D, Wegrzyn W, Musiał J.

II Katedra Chorób Wewnetrznych, Collegium Medicum UJ Kraków.

A 40-year-old man with Fabry disease, confirmed by decreased leukocyte alpha-galactosidase A activity in 2001, complained of sudden bilateral deafness, as evidenced by clinical history and audiometry. Magnetic resonance of the brain revealed features typical of Fabry disease. Other clinical manifestations of the disease included: angiokeratoma, mild proteinuria with normal renal function, lymphoedema of the lower limbs, pre-excitation syndrome, myocardial hypertrophy.



Alternative Titles: Fabry Disease


Fabry's Disease

What is Fabry's Disease?
Is there any treatment?
What is the prognosis?
What research is being done?


What is Fabry's Disease?
Fabry disease is a lipid storage disorder caused by the deficiency of an enzyme involved in the biodegradation of fats. The enzyme is known as ceramidetrihexosidase, also called alpha-galactosidase A. A mutation in the gene that controls this enzyme causes insufficient breakdown of lipids, which then build up in the body and cause a number of symptoms. The gene that is altered in this disorder is on the X-chromosome. If a woman has the mutated gene, her sons have a 50 percent chance of having the condition, and her daughters have a 50 percent chance of being a carrier. Symptoms of the disorder include burning sensations in the hands and feet that get worse with exercise and hot weather, and small, raised, reddish-purple blemishes on the skin. Some boys will also have eye manifestations, especially cloudiness of the cornea. As they grow older, they may have impaired arterial circulation leading to early heart attacks and strokes. The kidneys may become progressively involved, and require kidney transplantation or dialysis. A number of individuals have gastrointestinal difficulties characterized by frequent bowel movements shortly after eating. Some female carriers may also exhibit symptoms of the disorder.

Is there any treatment?
The pain in the hands and feet usually responds to medications such as Tegretol (carbamazepine) and dilantin. Gastrointestinal hyperactivity may be treated with metoclopramide or Lipisorb® (a nutritional supplement). Recent experiments indicate that enzyme replacement is effective therapy for patients with this disorder.

What is the prognosis?
Patients with Fabry disease usually survive into adulthood, but they are at risk for strokes, heart attacks, and kidney damage. It is anticipated that enzyme replacement and eventually gene therapy will eliminate these difficulties.

What research is being done?
NINDS supports research to find ways to treat and prevent lipid storage disorders such as Fabry disease.

Select this link  to view a list of all studies currently seeking patients.


Fabry disease

What is Fabry disease?

Fabry disease is caused by the lack of or faulty enzyme needed to metabolize lipids, fat-like substances that include oils, waxes, and fatty acids.  The enzyme is known as ceramide trihexosidase, also called alpha-galactosidase-A.  A mutation in the gene that controls this enzyme causes insufficient breakdown of lipids, which build up to harmful levels in the eyes, kidneys, autonomic nervous system, and cardiovascular system.  Since the gene that is altered is carried on a mother’s X chromosome, her sons have a 50 percent chance of inheriting the disorder and her daughters have a 50 percent chance of being a carrier.  Some women who carry the genetic mutation may have symptoms of the disease.  Symptoms usually begin during childhood or adolescence and include burning sensations in the hands that gets worse with exercise and hot weather and small, raised reddish-purple blemishes on the skin.  Some boys will also have eye manifestations, especially cloudiness of the cornea.  Lipid storage may lead to impaired arterial circulation and increased risk of heart attack or stroke.  The heart may also become enlarged and the kidneys may become progressively involved.  Other symptoms include decreased sweating, fever, and gastrointestinal difficulties, particularly after eating.  Fabry disease is one of several lipid storage disorders.

Is there any treatment?

Enzyme replacement may be effective in slowing the progression of the disease.  The pain in the hands and feet usually responds to anticonvulsants such as phenytoin and carbamazepine.  Gastrointestinal hyperactivity may be treated with metoclopramide.  Some individuals may require dialysis or kidney transplantation.

What is the prognosis?

Patients with Fabry disease often survive into adulthood but are at increase risk of strokes, heart attack and heart disease, and renal failure.

How common is Fabry disease?

This condition affects an estimated 1 in 40,000 to 117,000 live births. Milder forms of the disorder may be more common.

What genes are related to Fabry disease?

Mutations in the GLA gene cause Fabry disease.

The GLA gene makes an enzyme called alpha-galactosidase A. This enzyme is active in lysosomes, which are structures inside cells that digest and recycle particles that the cell doesn't need. The enzyme normally breaks down a particular molecule called globotriaosylceramide. Mutations in the GLA gene prevent alpha-galactosidase A from breaking down globotriaosylceramide, allowing it to build up in the body's cells. Over time, this buildup damages cells throughout the body, particularly blood vessels in the skin, kidneys, heart, and nervous system.

How do people inherit Fabry disease?

This condition is inherited in an X-linked recessive pattern. A condition is considered X-linked if the gene that causes the disorder is located on the X chromosome (one of the two sex chromosomes). In males, who have only one X chromosome, one altered copy of the gene is sufficient to cause the condition. In females, who have two X chromosomes, a mutation must be present in both copies of the gene to cause the disorder. Males are affected by X-linked recessive disorders much more frequently than females. A striking characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

In some cases, females with one altered copy of the GLA gene may have mild signs and symptoms related to the condition. Other women with one altered copy of the gene experience severe features of the disorder and require treatment.

Where can I find information about Fabry disease?

You may find the following resources about Fabry disease helpful.

You may also be interested in these resources, which are designed for healthcare professionals and researchers.

What other names do people use for Fabry disease?

  • Alpha-galactosidase A deficiency
  • Anderson-Fabry Disease
  • Angiokeratoma Corporis Diffusum
  • Angiokeratoma diffuse
  • Ceramide trihexosidase deficiency
  • Fabry's Disease
  • GLA deficiency
  • Hereditary dystopic lipidosis

What if I still have specific questions about Fabry disease?

Where can I find general information about genetic conditions?

What glossary definitions help with understanding Fabry disease?

ceramides ; chromosome ; complication ; deficiency ; enzyme ; gene ; heart attack ; lipid ; lysosome ; molecule ; mutation ; nervous system ; recessive ; sign ; symptom ; X-linked recessive

You may find definitions for these and many other terms in the Genetics Home Reference Glossary.

 References (3 links) 

The resources on this site should not be used as a substitute for professional medical care or advice. Users seeking information about a personal genetic disease, syndrome, or condition should consult with a qualified healthcare professional. See How can I find a genetics professional in my area? in the Handbook.



Alternative titles; symbols




Skin lesions of vascular nature are the basis of the name 'angiokeratoma.' Since angiokeratoma occurs with some other lysosomal diseases and may be missing in the disorder discussed here (see later), the use of the eponym 'Fabry disease' has much to recommend it, even though it ignores the important contribution of Anderson (1898). Fabry of Dortmund, Germany, wrote about the disorder first in 1898 and again in 1930. In his first paper, Fabry (1898) called the skin lesions 'purpura papulosa haemorrhagica Hebrae,' suggesting that they had previously been described by Hebra. Attacks of pain in the abdomen are often misdiagnosed as appendicitis or other 'surgical abdomen.' Such pains and those elsewhere, such as in the extremities, probably have their basis in lipid changes in ganglion cells of the autonomic nervous system. Vascular lesions of lipid nature occur at other sites such as the ocular fundi and kidney. Renal failure is the usual cause of death. Heterozygous females almost never have skin lesions and survive longer despite renal involvement. 

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. 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. The inclusion material was thought to be lipoid in nature. The findings resemble those of angiokeratoma corporis diffusum but the absence of other signs of this disease suggested that a new entity may be involved. The mother's father died of uremia. Skin lesions are easily overlooked. It is clear, however, that they may be lacking even in patients with severe visceral manifestations (Johnston, 1967); thus, the eponym Fabry disease is a better designation than angiokeratoma. Furthermore, identical angiokeratoma skin lesions occur in other lysosomal disorders: alpha-L-fucosidase deficiency (230000) (Patel et al., 1972); type II fucosidosis and a form of beta-galactosidase deficiency compatible with survival to adulthood (Loonen et al., 1974); occasionally aspartylglycosaminuria (208400); and an adult form of Schindler syndrome (104170). Flynn et al. (1972) described a family without skin lesions. One affected male had severe enteropathy. 

Franceschetti et al. (1969) reexamined the family with 'cornea verticillata' reported by Gruber (1946) and showed that Fabry disease was the 'cause' of the corneal change. The extent of involvement of the cornea is about the same in males and females. Thus, carrier females can be identified. The corneal condition was formerly called also Fleischer vortex dystrophy, or whorl-like corneal dystrophy. The antimalarial atabrine can produce a phenocopy. The antiarrhythmic drug amiodarone can also cause these changes (Stark, 1999). 

Mutoh et al. (1988) described an unusual degree of autonomic dysfunction, manifested by severe orthostatic hypotension, in a 21-year-old carrier. Rosenberg et al. (1980) pointed out that deposition of sphingolipid in epithelial cells of the respiratory tract leads to chronic obstruction of airflow. The effects are greatest in smokers. 

The observations of Ogawa et al. (1990), Elleder et al. (1990), and von Scheidt et al. (1991) indicate that manifestations of Fabry disease can be limited to the heart. Fabry disease should be considered in patients who have cardiac symptoms (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 alpha-galactosidase A 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 male hemizygotes who developed hypertrophic cardiomyopathy after the age of 50 as their first manifestation. The molecular defect in this late-onset variety is discussed in 301500.0003 and 301500.0005. Hillsley et al. (1995) described the case of 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. 

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. 

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). 

Ko et al. (1996) described a so-called 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. 

Halsted and Rowe (1975) described a 59-year-old man with Fabry disease. In addition to his unusually advanced age, he had celiac sprue. The last may have been related to the presence of the HLA-8 antigen, which is found in about 80% of persons with gluten-sensitive enteropathy. Peltier et al. (1977) reported male twins with Fabry disease but normal alpha-galactosidase and normality of several other lysosomal enzymes including alpha-fucosidase. 

Whybra et al. (2001) performed a comprehensive clinical evaluation on 20 carriers of 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. 

MacDermot et al. (2001) studied 98 males with Fabry disease. 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. Mean age at diagnosis was 21.9 years. Attendance at school, sports, and social activities were significantly affected by Fabry disease. Only 46 patients (56.6%) were employed. Psychosexual function was affected by the presence of genital angiokeratoma, genital pain, and impotence. 

Germain et al. (2002) concluded that progressive hearing loss and sudden deafness are frequent findings in Fabry disease. They investigated cochlear function in 22 hemizygous males (aged 19 to 64 years, mean 39) with classic Fabry disease. Abnormal hearing was found in 12 patients (54.5%): 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 their young age at time of examination. The incidence of hearing loss appeared significantly increased in Fabry disease patients with kidney failure (P less than 0.01) or cardiovascular lesions (P less than 0.01), whereas there was no correlation with left ventricular hypertrophy. Tinnitus aurium was found in 6 patients (27%). 

MacDermot et al. (2001) reported clinical manifestations and impact of disease in 60 obligate carrier females. 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. Nine of 32 (28%) died of cerebrovascular complications. Forty-two carriers (70%) had experienced neuropathic pain. Twenty carriers (30%) had some serious or debilitating manifestation of Fabry 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%. 


Kint (1970) showed that the activity of alpha-galactosidase is deficient in leukocytes of male patients with Fabry disease and that carrier 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 carriers of Fabry disease. Kirkilionis et al. (1991) described a Nova Scotia kindred known to contain 30 affected males and 50 possible female carriers. They found that there was no major alteration of the gene but that it was linked to the rarer allele (frequency = 0.20) of the polymorphic NcoI site located 3-prime to the gene. This helped carrier identification; all of 17 obligate carriers examined were identified, including 6 who were not identified as carriers by enzyme assay. 


In 2 patients, Mapes et al. (1970) demonstrated a decline in the plasma level of galactosylgalactosylglucosylceramide when normal plasma was infused to provide active enzyme (ceramide trihexosidase). Clement et al. (1982) reported that successful renal transplantation not only corrects the anemia but also produces marked improvement in other clinical manifestations of the disease. 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. 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. Findings in other reports have not been as satisfactory. For example, 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. It is intriguing to speculate that in the successful cases there was not a complete absence of enzyme so that antibodies did not develop as they may have in the case of Faraggiana et al. (1981). Hasholt and Sorensen (1986) found that GLA enzyme activity is particularly high in endothelial cells cultured from umbilical cord and absent in hemizygotes, thus accounting for the characteristic pathology of Fabry disease. 

To develop effective enzyme replacement therapy for Fabry disease, Schiffmann et al. (2000) designed a clinical trial to establish the safety and pharmacokinetics of intravenously-administered alpha-galactosidase A produced by transfection of human skin fibroblasts. 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 (GB3; also referred to as ceramidetrihexoside) levels in the patients after a single dose of alpha-galactosidase A. 

In preclinical studies of enzyme replacement therapy for Fabry disease in alpha-Gal A-deficient mice produced by homologous recombination in embryonic stem cells, Ioannou et al. (2001) demonstrated the dose-dependent clearance of tissue and plasma globotriaosylceramide, thereby providing the in vivo rationale, as well as critical pharmacokinetic and pharmacodynamic data, for the design of enzyme replacement trials in patients with Fabry disease. 

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.

Qin et al. (2001) reported marked improvement in the efficiency of the gene therapy approach for Fabry disease described by Takenaka et al. (2000)(see later): ex vivo transduction and transplantation of hematopoietic cells in a mouse model. Qin et al. (2001) used a novel bicistronic retroviral vector that engineers expression of both the therapeutic alpha-Gal A 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. 

Two differently produced enzyme preparations have independently been examined in clinical investigations for the treatment of Fabry disease: 1 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). It has 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. Blom et al. (2003) analyzed the occurrence of alpha-Gal A editing, as well as the precise nature, in this respect, of the therapeutic enzymes. No indications were obtained for the existence of editing at the protein or RNA levels. Both recombinant enzymes used in therapy were unedited and were capable of functionally correcting cultured fibroblasts from Fabry disease patients in their excessive globotriaosylceramide accumulation. 

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. Studies of residual activities of mutant enzymes in many Fabry disease patients have shown that some of the enzymes have kinetic properties similar to those of normal alpha-Gal A, 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. 

Roudebush et al. (1973) may have reported the first cases of 'abbreviated PR interval' in Fabry disease. A shortened PR interval may be related to the development of tachyarrhythmias and sudden death (Efthimiou et al., 1986). 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. This was based on observation of 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 (a recombinant human alpha-glycosidase A) resulted in continuously decreased plasma globotriaosylceramide (GL-3) levels, sustained endothelial GL-3 clearance, stable kidney function, and a favorable safety profile. 


Johnston et al. (1969) estimated the recombination fraction of angiokeratoma versus Xg to be 0.24 (95% probability limits, 8-49.8%) and of angiokeratoma versus deutan to be 0.17 (95% probability limits, 1-50%). The Fabry locus does 'lyonize' (Romeo and Migeon, 1970). Localization of the alpha-galactosidase (alpha-GAL; EC locus to the X chromosome had been achieved also by cell hybridization (Grzeschik, 1972). From study of radiation-induced segregants (irradiated human cells 'rescued' by fusion with hamster cells), Goss and Harris (1977) showed that the order of the following 4 loci is PGK--alpha-GAL--HPRT--G6PD and that the 3 intervals between these 4 loci are, in relative terms, 0.33, 0.30, and 0.23. Johnston and Sanger (1981) reanalyzed all data on Xg and Fabry linkage and obtained negative lod scores at all recombination rates. Alpha-GAL, HPRT, PGK and G6PD are X-linked in the rabbit, according to mouse-rabbit hybrid cell studies (Cianfriglia et al., 1979; Echard and Gillois, 1979). By comparable methods, Hors-Cayla et al. (1979) found them to be X-linked also in cattle. Francke and Taggart (1979) assigned HPRT and alpha-GAL to the X-chromosome in the Chinese hamster by study of mouse-Chinese hamster hybrid cells. MacDermot et al. (1987) found no recombination between Fabry disease and 3 DNA markers, DXS87, DXS88, and DXS17, which gave maximum lod scores of 6.4, 6.4, and 5.8, respectively, at theta = 0.00 (upper confidence limit 0.10). DXYS1 was not linked. 


By Southern analysis of the GLA gene in affected males from 130 unrelated families, Bernstein et al. (1989) found 6 with different gene rearrangements, and one with an exonic point mutation resulting in the obliteration of an MspI restriction site. 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. A sixth genomic rearrangement was identified in which a region of about 8 kb, containing exons 2-6, was duplicated by a homologous, but unequal crossover event. The MspI site obliteration, which mapped to exon 7, was found to result from a C-to-T transition at nucleotide 1066 in the coding sequence. The resulting change, the first point mutation identified in Fabry disease, resulted in an arg356-to-trp substitution, which altered the enzyme's kinetic properties and stability. Kornreich et al. (1990) assessed the 6 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 alpha-galactosidase A 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. 


The GLA gene is about 12 kb long and contains 7 exons encoding a precursor protein of 429 amino acids. The processed message for the entire alpha-galactosidase A subunit is about 1.45 kb long (Bishop et al., 1986). Bishop et al. (1988) cloned the entire GLA gene, characterized its intron-exon organization, and described the 5-prime regulatory elements and the 3-prime flanking sequence. The unusual lack of a 3-prime untranslated sequence in the GLA cDNA was confirmed. Kornreich et al. (1989) presented the complete nucleotide sequence of the GLA gene, including an extensive segment of 5-prime and 3-prime flanking sequences. 


Sakuraba et al. (1992) gave a useful listing of exon skipping and use of cryptic splice sites resulting from various mammalian (mainly human) 5-prime consensus splice site mutations. In the first exon of the GLA gene, which contains 60 bp of 5-prime untranslated sequence before the methionine initiation codon, Davies et al. (1993) demonstrated 3 polymorphic variants by SSCP screening. Such a high level of polymorphism had not previously been reported in the 5-prime untranslated region of the human gene and was unusual in such a short stretch of DNA. Davies et al. (1993) suggested that the polymorphisms should be of great assistance in family studies of angiokeratoma. 


Brown et al. (1997) pursued the suggested association between Fabry disease and airway obstruction by study of 25 unselected, consecutive, enzymatically diagnosed men. Dyspnea was a complaint in 36%, and 24% had cough and/or wheezing. 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 alpha-galactosidase A mutations were identified in 17 patients; all 3 patients with frameshift mutations and both subjects with the asp264-to-val mutation (310500.0021) 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. 


Romeo and Migeon (1970) presented evidence for a structural change in the mutant enzyme (slower heat inactivation than in the normal and different K(m) values).

Sawada et al. (1996) found a G-to-A transition in exon 6 of the GLA gene that resulted in an arg301-to-gln substitution (301500.0003) in a 45-year-old man who developed moderate proteinuria and was found to have the renal histologic findings of Fabry disease, together with a decrease in activity of alpha-galactosidase A in his plasma, urine, leukocytes, and skin fibroblasts. The mutation was inherited from his mother. The patient was unique in that he demonstrated only renal manifestations, whereas all other patients with atypical Fabry disease, including a case with the identical point mutation (Sakuraba et al., 1990), presented with cardiomyopathy. 

Nakao et al. (1995) found 7 unrelated patients with atypical variants of Fabry disease among 230 men with left ventricular hypertrophy. These 7 unrelated men, ranging in age from 55 to 72 years, did not have angiokeratoma, acroparesthesias, hypohidrosis, or corneal opacities. Endomyocardial biopsy, performed in 5 patients, revealed marked sarcoplasmic vacuolization in all 5. 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 exon 1 (301500.0051) and exon 6 (301500.0052). The remaining 5 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. Davies et al. (1993) found 7 putative disease-causing single base substitutions and 1 small insertion mutation 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. 

During a study of the GLA gene, Novo et al. (1995) found that RT-PCR amplification of alpha-galactosidase mRNAs obtained from 3 different tissues isolated from males revealed a substantial number of clones with a U2A conversion at nucleotide position 1187 of their sequence. Such a modification of the coding sequence would result in an amino acid substitution in the C-terminal region, phe396-to-tyr, of the enzyme. Neither PCR analysis of the genomic sequence nor the RT-PCR amplification of RNA obtained by in vitro transcription of the wildtype cDNA showed this change in the sequence. Multiple genes, pseudogenes, or allelic variants were excluded. Hence, Novo et al. (1995) proposed RNA editing as a mechanism responsible for this base change in the GLA RNA, similar to that which has been demonstrated for the nuclear encoded RNA for intestinal apoB (107730) and several subunits of brain L-glutamate receptors, such as GLUR2 (138247), GLUR5 (138245), and GLUR6 (138244). 

Blanch et al. (1996) amplified the 7 exons of the alpha-galactosidase A gene and the adjacent intron boundaries from a member of each of 9 kindreds and analyzed them for sequence alterations by SSCP analysis followed by sequencing. By this method they detected the causative mutations in 9 patients with classic severe Fabry disease. Counting a previously reported mutation, this strategy successfully detected all the mutations present in 10 kindreds analyzed. 

Germain et al. (1996) used the fluorescence-assisted mismatch analysis (FAMA) method to screen rapidly the GLA gene 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. They claimed that FAMA detected female heterozygous carriers 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. 

Germain (2001) described a patient with both Fabry disease due to the R342Q missense mutation in the GLA gene (301500.0030) and Klippel-Trenaunay-Weber syndrome (149000). The 30-year-old man had a complex vascular and cutaneous malformation. Skin examination showed numerous angiokeratomas, which had developed only on the right part of the body, with a sharp delineation in the midline of the trunk. The R342Q mutation was demonstrated in DNA extracted from fibroblast cultures established from both affected and unaffected skin areas, thus excluding the hypothesis of somatic mosaicism or revertant mosaicism. The patient had hypertrophy of the right leg, with dilated and varicose superficial veins. 

Branton et al. (2002) reviewed the medical records of 105 male infants with Fabry disease. They described the clinical course and histology of their renal disease and correlated them with residual alpha-galactosidase A activity and with mutations in the GLA gene. 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. They found that 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 (GB3). Conservative mutations in the GLA gene were also associated with a slower progression in Fabry renal disease. 

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. 

Yasuda et al. (2003) noted that the human GLA gene is one of the rare mammalian genes that has its polyadenylation signal in the coding sequence and lacks a 3-prime untranslated region. In 2 unrelated men with classic Fabry disease, they identified 2 novel frameshift mutations, 1277delAA (301500.0060) and 1284delACTT (301500.0061), which occurred in the 3-prime terminus of the coding region and obliterated the termination codon; the 2-bp deletion also altered the polyadenylation signal. Both mutations generated multiple transcripts of various lengths of 3-prime terminal sequences, some elongating approximately 1 kb. Mutant transcripts were classified into 3 types: type I transcripts had terminal in-frame thymidines that created termination codons when polyadenylated; type II had downstream termination codons within the elongated GLA sequence; and type III, the most abundant, lacked termination codons at their 3-prime ends. Yasuda et al. (2003) performed Northern blot analysis to determine if the type III transcripts were degraded by the cytosolic mRNA degradation pathway for messages lacking termination codons ('nonstop transcript decay'). They found similar levels of nuclear and cytoplasmic GLA mRNA in normal and patient lymphoblasts, suggesting that mRNA degradation did not result from either mutation. 

Lai et al. (2003) discussed the 5 major aberrant splicing patterns caused by mutations: exon skipping, cryptic site activation, new site creation, intron retention, and disruption of exonic splicing enhancers (Nakai and Sakamoto, 1994; Cooper and Mattox, 1997). The selection of splicing patterns is based on many factors. When no strong cryptic site or newly created site is available, destruction of either the donor or acceptor splice site causes skipping of the neighboring exon. This is the most important aberrant splicing pattern. Cryptic splice sites are normally silent consensus sites that are activated when the authentic site is destroyed by mutation. In general, the distance between the authentic site and the cryptic site is about 100 nucleotides long. Mutations also can result in the creation of a new splice site, which may or may not be associated with destruction of the authentic site. If the authentic site is not altered, the new splice site is always in the upstream region of the authentic site. Intron retention occurs infrequently and sometimes simultaneously with other splicing patterns. The retained introns are usually small. Exonic splicing enhancers also have a role in the regulation of splicing. The exonic splicing enhancer is a cis element, which has a distinct 5- to 7-nucleotide degenerate consensus that serves as a binding site for a class of splicing regulatory factors--arginine/serine-rich (SR) proteins--to facilitate splicing. See the report of Liu et al. (2001) showing that disruption of an exonic splicing enhancer resulted in missplicing of exon 18 in the BRCA1 gene (113705). Similar mechanisms may explain why many exonic missense or nonsense mutations that are not located at splice sites are associated with exon skipping. Lai et al. (2003) pointed out that most of the mutations in the GLA gene were identified in Fabry disease patients by genomic sequencing only, and therefore some of the splicing mutations were misclassified as missense mutations. To predict the splicing event caused by each mutation, they conducted a literature search for all published mutations located near the splice sites, including exonic point mutations, and performed a splice-site score (SSS) analysis. They found 13 donor-site mutations, including 4 exonic mutations (S65T, D183S, K213N, and M267I), located at the end of exons 1, 3, 4, and 5, respectively, 6 acceptor-site mutations, and 1 new exon creation. All mutated splice sites, except for the 1 associated with a new exon creation, had a lower SSS than their respective natural sites. For the S65T genotype (301500.0054), they performed RT-PCR analysis using RNA isolated from the whole blood sample. They verified that a weak cryptic site 14 nucleotides downstream was activated and resulted in an insertion of 14 bp and a frameshift stop at codon 106. This change was considered more consistent with the clinical presentation of the patient who had classic Fabry disease than the amino acid substitution (S65T), which did not affect enzyme function. 

Verovnik et al. (2004) reported the first Slovenian family with Fabry disease, in which an asn272-to-ser mutation in the GLA gene (N272S; 301500.0062) was identified in 7 males (including a set of twins) and 10 females. Affected members of the family demonstrated remarkable phenotypic heterogeneity. 


Ohshima et al. (1997) generated GLA-deficient mice by gene targeting. The knockout mice displayed a complete lack of alpha-galactosidase A activity but appeared clinically normal at 10 weeks of age. Ultrastructural analysis revealed concentric lamellar inclusions in the kidneys, and confocal microscopy using a fluorescent-labeled lectin specific for alpha-D-galactosyl residues showed accumulation of substrate in the kidneys as well as in cultured fibroblasts. Lipid analysis revealed a marked accumulation of ceramide trihexaside in the liver and the kidneys. The deficiency of enzyme activity and the accumulation of material containing terminal alpha-galactosyl residues in cultured embryonic fibroblasts derived from the knockout mice were corrected by transducing these cells with human GLA cDNA. 

Ohshima et al. (1999) characterized the progression of Fabry disease with aging in the GLA-deficient mice and explored the effects of bone marrow transplantation on the phenotype. Histopathologic analysis of the deficient mice showed subclinical lesions in the Kupffer cells in the liver and macrophages in the skin with no gross lesions in the endothelial cells. Accumulation of globotriaosylceramide (Gb3) and pathologic lesions in the affected organs increased with age. Treatment with bone marrow transplantation from wildtype mice resulted in the clearance of accumulated Gb3 in the liver, spleen, and heart with concomitant elevation of GLA activity. These findings suggested that bone marrow transplantation may have a role in the management of patients with Fabry disease. 

Overexpression of alpha-galactosidase A by transduced cells results in secretion of this enzyme. Secreted enzyme is available for uptake by nontransduced cells, presumably by receptor-mediated endocytosis. Correction of bystander cells may occur locally or systemically after circulation of the enzyme in the blood. Takenaka et al. (2000) reported studies on long-term genetic correction in an alpha-Gal A-deficient mouse model of Fabry disease. Enzyme-deficient bone marrow mononuclear cells (BMMCs) were transduced with a retrovirus encoding alpha-Gal A and transplanted into sublethally and lethally irradiated enzyme-deficient mice. Primary recipient animals were followed for up to 26 weeks. BMMCs were then transplanted into secondary recipients. Increased enzyme activity and decreased storage of globotriaosylceramide storage were observed in all recipient groups in all organs and tissues except the brain. These effects occurred even with a low percentage of transduced cells. The findings indicate that genetic correction of bone marrow cells derived from patients with Fabry disease may be useful for phenotypic correction of patients with this disorder. This approach might provide a long-term continuous source of enzyme for Fabry disease patients. 

Prigozy et al. (2001) found that splenic antigen-presenting cells from Gla-deficient mice could present alpha-galactosylceramide (alpha-GalCer) or 6-prime-linked alpha-GalGalCer, but not 2-prime-linked alpha-GalGalCer, to NK T-cell lines; these glycolipids are all presented by CD1D (188410) molecules. The authors also noted that Gla-deficient mice had a selective decrease in the number of splenic NK T cells and in their ability to respond to alpha-GalCer. 

Jung et al. (2001) investigated the possibility that delivery of the normal GLA gene (cDNA) into a depot organ such as the liver may be sufficient to elicit corrective circulating levels of the deficient enzyme. They constructed a recombinant adeno-associated virus (AAV) vector encoding the human enzyme and injected it into the hepatic portal vein of Fabry mice. Two weeks postinjection, enzyme activity in the livers of the injected mice was 20-35% of that in normal mice. The transduced animals continued to show higher enzyme levels in liver and other tissues compared with the untouched Fabry controls as long as 6 months after treatment. In parallel to the elevated enzyme levels, significant reductions occurred in globotriaosylceramide levels to near normal at 2 and 5 weeks posttreatment. The lower Gb3 levels continued in liver, spleen, and heart up to 25 weeks with no significant immune response to the virus or the enzyme. Also, no signs of liver toxicity occurred after the administration. Jung et al. (2001) suggested that an AAV-mediated gene transfer may be useful for the treatment of Fabry disease and possibly other metabolic disorders. 

Takahashi et al. (2002) used the AAV vector containing the alpha-Gal A gene in the treatment of Fabry disease in knockout mice. The vector containing the gene was injected into the quadriceps muscle. Elevated enzyme activity in plasma persisted for up to at least 30 weeks without development of antibodies. Enzyme activity in various organs of treated Fabry mice remained 5 to 20% of those observed in normal mice. Accumulated globotriaosylceramide in these organs was completely cleared by 25 weeks after vector injection. Echocardiographic examination of treated mice demonstrated structural improvement of cardiac hypertrophy 25 weeks after the treatment. 

(selected examples)


In a case of Fabry disease, Bernstein et al. (1989) identified a substitution of tryptophan for arginine-356 as a result of a C-to-T transition at nucleotide 1066.


Fukuhara et al. (1990) reported partial deletion of the GLA gene in a case of Fabry disease. The deletion involved exon 3 and was associated with a single base change of A to C. The 402-bp deletion was flanked by 6-bp direct repeat sequences. These structures may have promoted 'slipped mispairing' as the origin of the mutation in this family. 


In a Japanese patient with Fabry disease following an atypical clinical course characterized by late-onset cardiac involvement and significant residual alpha-galactosidase A activity, Sakuraba et al. (1990) identified a G-to-A transition in exon 6 (codon 301) resulting in replacement of an arginine residue by glutamine. The same mutation was observed by Sawada et al. (1996) in a 45-year-old man with nephropathy as the only manifestation. 

Kase et al. (2000) characterized this mutant and another, Q279E (301500.0008), which likewise causes the cardiac variant of Fabry disease. In contrast to patients with classic Fabry disease, who have no detectable alpha-galactosidase activity, patients with these variants have residual enzyme activity. Compared to normal control cells, fibroblasts from a patient with the Q279E mutation secreted only small amounts of alpha-galactosidase. The authors concluded that these 2 substitutions do not significantly affect enzymatic activity, but the mutant protein levels are decreased presumably in the endoplasmic reticulum of cells. 30 MEDLINE Neighbors


In a Japanese patient with classic Fabry disease and no detectable alpha-galactosidase A activity, Sakuraba et al. (1990) found a G-to-A transition in exon 1 (codon 44) which substituted a termination codon (TAG) for a tryptophan codon (TGG) and created an NheI restriction site. The point mutation predicts a truncated enzyme protein, consistent with the observed absence of enzymatic activity and the classic Fabry phenotype. 


In a 54-year-old man with 'crescendo angina,' relieved by nitroglycerin, von Scheidt et al. (1991) found 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. The molecular defect was shown by von Scheidt et al. (1991) to be an A-to-G transition at nucleotide 886 in exon 6 resulting in a methionine-to-valine substitution at residue 296. 


In an 11-year-old boy with Fabry disease, Yokoi et al. (1991) identified a G-to-A mutation at the 3-prime consensus sequence (splicing acceptor) of intron 3. The mutation resulted in deletion of exon 4 and a frameshift with appearance of a terminating codon in exon 5.


In a Japanese family with 3 classically affected brothers, Sakuraba et al. (1992) identified deletion of exon 6 due to a G-to-T transversion at the first nucleotide of the 5-prime splice site of intron 6. Sakuraba et al. (1992) stated that this was the first G-to-T transversion of a mammalian 5-prime splice site that consistently eliminated the preceding exon. Sakuraba et al. (1992) gave a tabulation of various mammalian 5-prime consensus splice site mutations that lead to exon skipping and in most cases use of cryptic splice sites. They pointed out that glycophorin B of the Ss blood group (111740) differs from glycophorin A of the MN blood group (111300) by 2 changes at the 5-prime splice site of intron 3 which presumably took place after duplication of the progenitor gene. As indicated in their Table 1, the gene for growth hormone-like (GH2; 139240) differs from that for growth hormone (GH1; 139250) by a G-to-A transition at position +1 of intron 2 in the duplicated gene (Chen et al., 1989). 


Ishii et al. (1992) identified an 835C-G transversion in the GLA gene, resulting in a gln279-to-glu substitution, in a Japanese patient who developed dyspnea and bradycardia for the first time at 60 years of age. He was found to have complete left bundle branch block associated with hypertrophy of the left ventricular wall and interventricular septum. He died of heart failure at age 64. He had no other signs or symptoms characteristic of Fabry disease except proteinuria, which was found after cardiac failure had developed. Myocardial biopsy had shown inclusion bodies on electron microscopic examination. A 39-year-old nephew was asymptomatic but showed a thick interventricular septum and left ventricular wall by echocardiography and magnetic resonance imaging. Both men had some residual alpha-galactosidase A activity. The mutation in this case, as in 2 other cases of the cardiac form (301500.0003, 301500.0005), was located in exon 6. On the other hand, the gly328-to-arg mutation, located at the 3-prime end of exon 6 was associated with classic features of Fabry disease (see 301500.0010). 


Koide et al. (1990) described a pro40-to-ser mutation in exon 1 in a patient with Fabry disease and no detectable alpha-galactosidase A activity.


In a 34-year-old man with typical Fabry disease, Ishii et al. (1992) identified a G-to-A transition at nucleotide 982 of the GLA gene, resulting in substitution of arginine for glycine-328. This mutation was located at the 3-prime end of exon 6; mutations located at the central or 5-prime end of the exon were associated with the predominantly cardiac form of the disease. 


In a 14-year-old boy with classic Fabry disease, Ishii et al. (1992) found 2 point mutations in exon 2 of the GLA gene: a GAG-to-CAG change causing a glu66-to-gln substitution, and a CGC-to-TGC change causing an arg112-to-cys substitution.


In a patient with classic Fabry disease, Eng et al. (1993) found an AAT-to-AGT mutation at codon 34 of exon 1 resulting in substitution of serine for asparagine.


In an English patient with classic Fabry disease, Eng et al. (1993) found a TGC-to-GGC mutation at codon 56 of exon 1 resulting in substitution of glycine for cysteine.


In a Dutch patient with mild Fabry disease, deJong et al. (1993) found a CCT-to-TCT mutation at codon 146 of exon 3 resulting in a pro146-to-ser substitution.


In a Danish patient with classic Fabry disease, Madsen et al. (1993) found a GCC-to-ACC mutation at codon 156 of exon 3 resulting in an ala156-to-thr substitution.


In an Italian patient with classic Fabry disease, Eng et al. (1993) found a TGG-to-CGG mutation at codon 162 of exon 3 resulting in a trp162-to-arg substitution.


In a Dutch patient with classic Fabry disease, deJong et al. (1993) found a TGT-to-TGG mutation at codon 202 of exon 4 resulting in a cys202-to-trp substitution.


Eng et al. (1993) and Davies et al. (1993) have described an AAT-to-AGT mutation at codon 215 of exon 5 resulting in an asn215-to-ser substitution. The patients had mild forms of Fabry disease.


Eng et al. (1993) described a CGA-to-CAA mutation at codon 227 of exon 5 resulting in an arg227-to-gln substitution. The patients had classic Fabry disease. This mutation conforms to the CG-to-TG mutation 'hotspot' rule. (In the complementary, antisense strand, 5-prime--xxxCGAxxx--3-prime is read as 3-prime--xxxGCTxxx--5-prime. Methylation of the cytosine in the CpG of the antisense codon with subsequent deamidation converts the antisense codon to GTT, which corresponds to the sense codon CAA. Read 5-prime to 3-prime, the CG in the sense strand has been changed to TG in the antisense strand; hence, the designation CG-to-TG 'hotspot' rule.) 


Eng et al. (1993) and Davies et al. (1993) described a nonsense CGA-to-TGA mutation at codon 227 of exon 5. The mutation conforms to the CG-to-TG rule and results in classic Fabry disease. This mutation has been found in more than 1 unrelated patient.


In a Scottish/English patient with classic Fabry disease, Eng et al. (1993) found a GAC-to-GTC mutation at codon 264 of exon 5 resulting in substitution of valine for asparagine.


In an African-American patient with classic Fabry disease, Eng et al. (1993) found a GAT-to-GTT mutation at codon 266 of exon 5 resulting in an asp266-to-val substitution.


In an English patient with classic Fabry disease, Davies et al. (1993) found a GTG-to-GCG mutation at codon 269 of exon 6 resulting in a val269-to-ala substitution.


In an English patient with classic Fabry disease, Davies et al. (1993) found a TGG-to-TGA nonsense mutation at codon trp287 of exon 6.


In an Italian patient with classic Fabry disease, Eng et al. (1993) found a TCT-to-TTT mutation at codon 297 of exon 6 resulting in a ser297-to-phe substitution.


In a German patient with classic Fabry disease, Eng et al. (1993) found a GAT-to-TAT mutation at codon 313 of exon 6 resulting in an asp313-to-tyr substitution.


In an English patient with classic Fabry disease, Davies et al. (1993) found a CAA-to-AAA mutation at codon 327 of exon 6 resulting in a glu327-to-lys substitution.


In a Scottish/Irish patient with classic Fabry disease, Eng et al. (1993) found a GGG-to-GCG mutation at codon 328 of exon 6 resulting in a gly328-to-ala substitution. A different mutation has also been described in the same codon (see 301500.0010).


In an African-American patient with classic Fabry disease, Eng et al. (1993) found a nonsense TGG-to-TGA mutation at codon 340 of exon 7.


In a Dutch patient with classic Fabry disease, deJong et al. (1993) found a CGA-to-CAA mutation at codon 342 of exon 7 resulting in an arg342-to-glu substitution. This mutation conforms to the CG-to-TG 'hotspot' rule.

This mutation was found by Germain (2001) in a patient who had Fabry disease and Klippel-Trenaunay-Weber syndrome (149000).


In a Greek/English patient with classic Fabry disease, Davies et al. (1993) found a nonsense CGA-to-TGA mutation at codon 342 of exon 7.


In an English patient with classic Fabry disease, Davies et al. (1993) found a GGA-to-CGA mutation at codon 361 of exon 7 resulting in a gly361-to-arg substitution.


In an Hispanic patient with classic Fabry disease, Eng et al. (1993) found a nonsense GAA-to-TAA mutation at codon 398 of exon 7.


In a Sephardic Jewish patient with classic Fabry disease, Eng et al. (1993) found a T-to-G mutation at nucleotide +2 of the donor splice site of intron 2.


In an Irish patient with classic Fabry disease, Eng et al. (1993) found a deletion of 2 nucleotides (-2 and -3) of the acceptor splice site of intron 5. The mutation is therefore tcag/exon 6 to tg/exon 6.


In a Japanese patient with severe Fabry disease, Ishii et al. (1991) found a deletion of 13 bp in exon 1 starting at nucleotide 125. The deletion is flanked by a TGGG direct repeat.


In an English patient with severe Fabry disease, Davies et al. (1993) found a deletion of 1 bp at nucleotide 716 of exon 5.


In a Portuguese patient with severe Fabry disease, Eng et al. (1993) found a deletion of 2 bp at nucleotide 773 of exon 5.


In a German patient with severe Fabry disease, Eng et al. (1993) found an insertion of 5 bp starting at nucleotide 954 of exon 6.


In a German patient with severe Fabry disease, Eng et al. (1993) found a deletion of 11 bp starting at nucleotide 1016 of exon 7.


In a Dutch patient with severe Fabry disease, deJong et al. (1993) found an insertion of 1 nucleotide at nucleotide 1040 of exon 7.


In a Dutch patient with severe Fabry disease, Eng et al. (1993) found a deletion of 53 bp starting at nucleotide 1123 of exon 7.


In a Dutch patient with severe Fabry disease, deJong et al. (1993) found a deletion of 2 bp at nucleotide 1176 of exon 7. The deletion had a 6-bp inverted repeat at the breakpoint junction.


In an English patient with moderate Fabry disease, Eng et al. (1993) found a deletion of AAG starting at nucleotide 1208 of exon 7. The sequence at the deletion site is AAGAAG and the deleted 3 nucleotides cannot be exactly defined. The mutation results in deletion of arg405.


In a Slavic patient with severe Fabry disease, Kornreich et al. (1990) found a 4.6-kb deletion that included exons 1 and 2 of the gene. The deletion breakpoints had a CCA direct repeat suggesting a possible functional role of this short sequence in illegitimate recombination.


In an Hispanic family with severe Fabry disease, Kornreich et al. (1990) found a 3.2-kb deletion that included exons 3 and 4 of the gene. The 2 breakpoints occurred in Alu repetitive elements and Alu-Alu recombination is the probable mechanism of this deletion.


In an English patient with severe Fabry disease, Kornreich et al. (1990) found a 4.5 kb-deletion that included exons 3 to 6 and a portion of exon 7. The deletion breakpoints had an AAG direct repeat suggesting a possible functional role of this short sequence in illegitimate recombination.


In an Irish/German patient with severe Fabry disease, Kornreich et al. (1990) found a deletion of 1.7 kb that included exons 6 and 7 of the gene.


In an English patient with severe Fabry disease, Kornreich et al. (1990) found a duplication of 8.1 kb that included exons 2 to 5 and part of exon 6 of the gene. The duplicated area was flanked by a TAGACA direct repeat.


In a study of left ventricular hypertrophy in Japan, Nakao et al. (1995) found 7 of 230 males (3%) with low plasma alpha-galactosidase activity but none of the typical manifestations of Fabry disease, namely angiokeratoma, acroparesthesias, hypohidrosis, and corneal opacities. One of the patients had a met296-to-ile mutation in exon 6, whereas a second had an ala20-to-pro mutation in exon 1 (310500.0052). 


See 301500.0051.


Cariolou et al. (1996) described a novel trinucleotide deletion in a Greek patient with Fabry disease. This deletion led to loss of phenylalanine-383. The phenotype in this patient was unusual in that diffuse facial telangiectasia occurred.


In 2 unrelated Chinese patients with Fabry disease, living in Taiwan, Chen et al. (1998) identified a G-to-C transversion in the last nucleotide of exon 1 which not only changed serine-65 to threonine, but probably also caused a splicing defect.

Lai et al. (2003) demonstrated that this missense mutation, S65T, does not affect enzyme function. Instead it results in activation of a weak cryptic site 14 nucleotides downstream and results in an insertion of 14 bp and a frameshift stop at codon 106. This splicing abnormality was thought to be more consistent with the clinical presentation of the patient with classic Fabry disease. 


In a family with Fabry disease, Miyamura et al. (1996) identified a novel mutation of the GLA gene, which converted a tyrosine at codon 365 to a stop (tyr365ter) and resulted in a truncation of the C terminus by 65 amino acid residues. In a heterozygote of this family, although the mutant and normal alleles were equally transcribed in cultured fibroblasts, lymphocyte alpha-galactosidase A activity was approximately 30% of the normal control, and severe clinical symptoms were apparent. COS-1 cells transfected with this mutant cDNA showed a complete loss of its enzymatic activity. Furthermore, cells cotransfected with mutant and wildtype cDNAs showed approximately 30% of the enzyme activity of those with wildtype alone, which suggested a dominant-negative effect of this mutation and implied the importance of the C terminus for its activity. Generating mutant cDNAs with various deletions of the C terminus, Miyamura et al. (1996) found that enzyme activity was enhanced up to 6-fold compared with wildtype when 2 to 10 amino acid residues were deleted. In contrast, deletion of 12 or more amino acid residues resulted in a complete loss of enzyme activity. These data suggested that the C-terminal region of the GLA protein plays an important role in the regulation its enzyme activity. 


During the course of mutation analysis of a patient with the cardiac form of Fabry disease who had residual enzyme activity 9.1% of normal in lymphoblasts, Ishii et al. (2002) were unable to identify any mutation in the exonic or flanking intronic regions of the GLA gene. By RT-PCR of the RNA and direct sequencing of the RT-PCR product, they found an insertion between exons 4 and 5. To characterize further the abnormal splicing, they sequenced intron 4 (nucleotides 8413-10130) of the GLA gene and identified a G-to-A transition at nucleotide 9331 (IVS4+919G-A). This change was not found in 100 unaffected Japanese males. The mutation in the middle of the intron increased the recognition of a normally weak splice site, resulting in the insertion of an additional sequence into the GLA transcript and leading to the cardiac phenotype of Fabry disease. 


In 4 patients of Nova Scotian ancestry with no known genealogic connection, Branton et al. (2002) found an ala143-to-pro (A143P) missense mutation in exon 3 of the GLA gene. Three of the patients were French Acadian; the fourth had a Greek surname but may also have been of French Acadian ancestry (Kopp, 2002). 


In a Chinese family, Yang et al. (2003) identified a nonsense mutation in the GLA gene, a C-to-A transversion resulting in an early termination at amino acid 22 (tyr222 to stop; Y222X). The genotype was associated with classic Fabry disease, with unexpectedly rapid deterioration of visual acuity. 


In a Chinese family, Yang et al. (2003) identified an A-to-G transition, resulting in the substitution of alanine for threonine at amino acid 410 (thr410 to ala; T410A). The T410A mutation was associated with a milder form of Fabry disease, with ventricular hypertrophy and neuropathic pain.


In a patient with classic Fabry disease, Yasuda et al. (2003) identified a 2-bp deletion, 1277delAA, causing frameshift, in the GLA gene. The patient was a 51-year-old Swedish man who had onset of acroparesthesias at 10 years of age and subsequently had gastrointestinal manifestations, including abdominal pain and chronic diarrhea. He developed hypertrophic cardiomyopathy and, because of atrial ventricular block, required a pacemaker. His renal function was normal, with only a trace of urinary protein. 


In a patient with classic Fabry disease, Yasuda et al. (2003) identified a 4-bp deletion, 1284delACTT, in the GLA gene. The patient was a 51-year-old Brazilian man who had childhood onset of acroparesthesias, angiokeratoma, hypohidrosis, and corneal opacities. He had microalbuminuria, which may have been secondary to his diabetes mellitus, but retained normal renal function. He had no evidence of cardiac or cerebral involvement. 


In affected members of a Slovenian family with Fabry disease, Verovnik et al. (2004) identified a 10523A-G transition in exon 6 of the GLA gene, resulting in an asn272-to-ser (N272S) substitution. The 7 affected males (including a set of twins) showed decreased to absent alpha-galactosidase activity and had symptoms of classic Fabry disease, but there was considerable variability in their organ involvement, particularly renal: 3 were on dialysis, but 4 had only mild to moderate proteinuria. The 10 female carriers had much milder symptoms, with no renal failure, severe cardiac disease, or stroke. Verovnik et al. (2004) stated that this was the first reported Slovenian family with Fabry disease. 


Bach et al. (1982); Beaudet and Caskey (1978); Bird and Lagunoff (1978); Brady et al. (1967); Broadbent et al. (1981); Cable et al. (1982); Cable et al. (1982); Calhoun et al. (1985); Colucci et al. (1982); Davies et al. (1993); Eng et al. (1993); Friedman et al. (1984); Frost et al. (1966); Gruber (1946); Hamers et al. (1979); Kornreich et al. (1989); Lusis and West (1976); MacDermot et al. (1987); Maisey and Cosh (1980); O'Brien (1980); Opitz et al. (1965); Philippart et al. (1969); Pierides et al. (1976); Pyeritz et al. (1980); Rahman et al. (1961); Rodriguez et al. (1985); Ropers et al. (1977); Sakuraba et al. (1986); Sheth et al. (1981); Shows et al. (1978); Sorensen and Hasholt (1980); Spence et al. (1978); Spence et al. (1976); Sweeley and Klionsky (1963); Tagliavini et al. (1982); Wise et al. (1962)




Description of a new mutation in a female patient with Fabry disease.

Oct 2011

[Article in Portuguese]
Correia E, Vidinha J, Rodrigues B, Santos L, Moreira D, Garrido J, Clara Sá Miranda M, Cabral C, Santos O.


Serviço de Cardiologia, Centro Hospitalar Tondela Viseu, Portugal.


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



Value of Electrocardiogram in the Differentiation of Hypertensive Heart Disease, Hypertrophic Cardiomyopathy, Aortic Stenosis, Amyloidosis, and Fabry Disease

Nov 2011



Colonic Involvement in Fabry Disease

Nov 2011


Angiokeratoma: Decision Making Methodology for the Diagnosis of Fabry Disease. 

Nov 2011


Globotriaosylceramide is correlated with oxidative stress and inflammation in Fabrypatients treated with enzyme replacement therapy 

Nov 2011


Histologic abnormalities of placental tissues in Fabry disease: a case report and review of the literature. 

Nov 2011


The use of high resolution melting analysis to detect Fabry mutations in heterozygous females via dry bloodspots. 

Oct 2011


Simultaneous multicystic kidney and Anderson-Fabry disease: 2 separate entities or same side of the coin. 

Nov 2011


Female Anderson-Fabry disease mimicking hypertrophic cardiomyopathy. 

Nov 2011


Stroke and Fabry disease. 

Oct 2011


Interdisciplinary approach towards female patients with Fabry disease

Oct 2011


Fabry disease, enzyme replacement therapy and the significance of antibody responses. Oct 2011


Therapy of Fabry disease with pharmacological chaperones: from in silico predictions to in vitro tests. 

Oct 2011


External Links:




Focus on Fabry


Fabry Community


L’Association des Patients de la Maladie de Fabry (APMF)


International Center for Fabry Disease


Canadian Fabry Association


Fabry Support & Information Group
108 NE 2nd Street, Suite C
Concordia, MO 64020
Tel: 660-463-1355
Fax : 660-463-1356


National Tay-Sachs and Allied Diseases Association
2001 Beacon Street
Suite 204
Brighton, MA 02135
Tel: 617-277-4463 800-90-NTSAD (906-8723)
Fax: 617-277-0134


Fabry Registry


Fabry England - The Society for Mucopolysaccharide Diseases


APMF - Fabry Disease Patient Association - France


Fabry - Norway


Fabry Support & Informatie Groep Nederland


Fabry - Swiss


Fabry Quebec


Lysosomal Storage Disorders - France


Global Organization for Lysosomal Diseases (GOLD)

ADAC - Spanish Association for Growth and Lysosomal Diseases

Association for Growth, Developmental and Lysosomal Disorders
Enrique Marco Dorta 6
41018 Seville
Tel +34 954 989 889


Polish MPS Society
ul. Radnych 9A
05-503 Gloskow, Poland
Tel +48 22 715 3319


Malaysia Metabolic Society (Persatuan Metabolik Malaysia)



Additional Resources

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
National Institutes of Health, DHHS
31 Center Drive, Rm. 9A06 MSC 2560
Bethesda, MD 20892-2560
Tel: 301-496-3583


National Organization for Rare Disorders (NORD)
P.O. Box 1968
(55 Kenosia Avenue)
Danbury, CT 06813-1968
Tel: 203-744-0100 Voice Mail 800-999-NORD (6673)
Fax: 203-798-2291


Association for Neuro-Metabolic Disorders
c/o Cheryl Volk
5223 Brookfield Lane
Sylvania OH 43560
Tel: 419-885-1497


Lipid Storage Diseases Fact Sheet


Pharmaceutical Companies

Amicus Theraputics, Inc.
Shire Pharmaceuticals Group


Codes and Classifications:



E75.2 Other sphingolipidosis
· Fabry(-Anderson)
· Gaucher
· Krabbe
· Niemann-Pick
Farber's syndrome
Metachromatic leukodystrophy
Sulfatase deficiency
Excludes: adrenoleukodystrophy [Addison-Schilder] ( E71.3 )


2008 ICD-9-CM Diagnosis 272.7


  • A disturbance of lipid metabolism with abnormal deposit of lipids in the cells. (Dorland, 27th ed)
  • A group of diseases marked by autosomal recessive inheritance and accumulation of sphingomyelin in cells of the RETICULOENDOTHELIAL SYSTEM. They are divided into 5 subtypes: A-E. Type A (classic infantile form) is caused by a deficiency of SPHINGOMYELIN PHOSPHODIESTERASE and presents at age 6-12 months with progressive hepatosplenomegaly and neurologic deterioration. Type B (non-neuronopathic form) presents in childhood with hepatosplenomegaly and pulmonary infiltrates. Type C (chronic neuronopathic form) is caused by defective intracellular cholesterol transport and is divided into severe infantile, late infantile, juvenile, and neonatal hepatitis forms. Type D (Nova Scotian Variant) is phenotypically similar to type C. Type E is an adult non-neuronopathic form. (From Menkes, Textbook of Child Neurology, 5th ed, pp101-4)
  • An autosomal recessive disorder caused by deficiency of the enzyme glucocerebrosidase (see GLUCOSYLCERAMIDASE) featuring the pathological storage of glycosylceramide in mononuclear PHAGOCYTES (Gaucher Cells). The most common subtype is the non-neuronopathic form, a slowly progressive condition characterized by hepatosplenomegaly and skeletal deformities. The neuronopathic forms are divided into infantile and juvenile forms. The infantile form presents at 4-5 months of age with anemia, loss of cognitive gains, neck retraction, dysphagia, and hepatosplenomegaly. The juvenile form features a slowly progressive loss of intellect, hepatosplenomegaly, ATAXIA, myoclonic SEIZURES, and spasticity. The neuronopathic forms are characterized by neuronal loss with neuronophagia, and accumulation of glucocerebroside in neurons. (From Baillieres Clin Haematol 1997 Dec;10(4):711-23; Menkes, Textbook of Child Neurology, 5th ed, p97)
  • Intestinal fat transport defect with hypobetalipoproteinemia and accumulation of apolipoprotein B-like protein in intestinal cells, deficient blood apolipoproteins, and avitaminosis E manifested by malnutrition, steatorrhea, and growth and mental retardation. Some clinical (but not biochemical) manifestations may disappear later in life.
  • Lysosomal storage disease caused by a deficiency of alpha-galactosidase A and resulting in an accumulation of globotriaosylceramide in the renal and cardiovascular systems. The disease is X-linked and is characterized by telangiectatic skin lesions, renal failure, and disturbances of the cardiovascular, gastrointestinal, and central nervous systems.
  • The severe infantile form of inherited lysosomal lipid storage diseases, due to deficiency of acid lipase. It results in accumulation of neutral lipids, particularly cholesterol esters, within cells (particularly leukocytes, fibroblasts, and liver cells). An allelic variant of CHOLESTEROL ESTER STORAGE DISEASE, it is also known as Wolman's xanthomatosis.
  • 272.7 is a specific code that can be used to specify a diagnosis
  • 272.7 contains 82 index entries
  • View the ICD-9-CM Volume 1 272.* hierarchy

272.7 also known as:

  • Chemically induced lipidosis
  • Disease:
    • Anderson's
    • Fabry's
    • Gaucher's
    • I cell [mucolipidosis I]
    • lipoid storage NOS
    • Niemann-Pick
    • pseudo-Hurler's or mucolipidosis III
    • triglyceride storage, Type I or II
    • Wolman's or triglyceride storage, Type III
  • Mucolipidosis II
  • Primary familial xanthomatosis

272.7 excludes:

  • cerebral lipidoses (330.1)
  • Tay-Sachs disease (330.1)

OMIM 301500

eMedicine neuro/579

MeSH D000795

Gene:  GLA (galactosidase, alpha).


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