Anderson Fabry Disease

Author: Simona Perga
Date: 03/07/2010


Nicola Corino, Francesco De Amicis, Giulia Gay, Simona Perga


Fabry disease (also known as Anderson-Fabry disease (AFD), angiokeratoma corporis diffusum and alpha-galactosidase A deficiency), is a rare, X-linked lysosomal storage disorder (LSD), caused by an inborn deficiency of α-galactosidase A (α-Gal A). The resulting inability to catabolise glycosphingolipids causes progressive accumulation of globotriaosylceramide (CTH, Gb3, or GL-3) in endothelial cells, vascular smooth muscle, erector pilori muscles in the skin, myocardium, corneal epithelial cells and in organs such as the kidney, pancreas, bowel and lung. The resulting symptoms usually appear during childhood and adolescence, affect many organ systems and may lead to progressive disease and premature death.


Fabry disease (also known as Fabry's disease, Anderson-Fabry disease, angiokeratoma corporis diffusum and alpha-galactosidase A deficiency) is a rare X-linked recessive (inherited) lysosomal storage disease, which can cause a wide range of systemic symptoms. It was first described independently in 1898 by Anderson and Fabry but the enzyme deficiency was not defined until the 1960s.
This disorder is caused by deficient activity of lysosomal enzyme alpha-galactosidase A (alpha-Gal A). This enzymatic defect leads to the systemic accumulation of neutral glycosphingolipids, especially globotriaosylceramide (Gb3), in the plasma and cellular lysosomes throughout the body tissues such as in vascular endothelial and smooth muscle cells, epithelial, perithelial, myocardial, gangliar, perineural and rethiculoendothelial cells and to a lesser extent of blood group antigen B (of the ABO blood group antigens) derived compounds, causing abnormalities in skin, eye, kidney, heart, brain and peripheral nervous system. The mechanism by which this accumulation causes symptoms of disease is still unknown. This disease belongs to the family of lysosomal storage diseases (Cartoon). Lysosomal storage diseases (LSDs) comprise a group of at least 50 distinct genetic diseases, each one resulting from a deficiency of a particular lysosomal protein/activity or, in a few cases, from non-lysosomal activities that are involved in lysosomal biogenesis or protein maturation and Fabry disease is the second most common of the LSDs, after Gaucher disease. Other diseases in this family include Niemann-Pick disease, Farber diseaser the gangliosidoses (including Tay-Sachs disease), Krabbé disease/Krabbé_disease action=edit&redlink=1, and Wolman’s disease


The Diseases DatabaseURL
OMIM single geneFabry


Genetics and epidemiology

Fabry disease it's a rare panethnic.disorder: the estimate incidence range from 1 in 40,000 males8, to 1 in 117,000 in the general population.
The true incidence is underestimated, however, as there are paucisintomatic types which occur with isolated or primary involvement setting cardiac, renal, cerebrovascular "variants". Although genetic transmission is linked to the X chromosome, females can be equally affected, often with paucisintomatic features and late onset.
As an X-linked recessively inherited condition female carriers exist and can exhibit mild to moderate symptoms (variable expression according to random X inactivation of the affected gene in embryogenesis).


The gene for alpha-galactosidase A (GLA gene) is located on the long arm of the chromosome X, in the region q22.1. It is approximately 12 kb and contains 7 exons that are associated with extensive 5’ regulatory and 3’ flanking sequences. The GLA gene encodes for a homodimeric glycoprotein that hydrolyses the terminal alpha-galactosyl moieties from glycolipids and glycoproteins.
To date, more than 370 mutations have been identified in people with Fabry disease. Most of these genetic changes are small deletions or insertions and numerous single based substitutions leading to missense or nonsense mutations.
Although some generalizations are possible, attempts to identify specific genotype-phenotype correlations have not been very successful.
Mutations that cause clinical disease are invariably associated with marked deficiency of alpha-galactosidase A activity.
The mutations are usually ‘private’ (restricted to a single or few families) and usually lead to complete lack of detectable enzyme. Alterations in the GLA gene produce an abnormal version of the enzyme that is unable to break down globotriaosylceramide effectively. As a result, this substance builds up in the body's cells, particularly cells lining blood vessels in the skin and cells in the kidneys, heart, and nervous system. The progressive accumulation of globotriaosylceramide damages these cells, leading to the varied signs and symptoms of Fabry disease. Mutations that eliminate the activity of the alpha-galactosidase A enzyme lead to the severe, classic form of Fabry disease, which typically begins in childhood. Mutations that reduce but do not completely eliminate the enzyme's activity usually cause milder, late-onset forms of the disorder.
However, as little as 5% to 10% residual enzyme activity seems to be sufficient to prevent clinically significant Gb3 accumulation, a fact that is particularly important when efforts are undertaken to treat the disease with ERT or enzyme enhancement therapy.


Since the alpha-Gal A gene is located on the X chromosome the inheritance of AFD consequently follows an X-linked pattern. Hemizygous males carry a defective X-chromosome and develop classical AFD. Heterozygous females have one normal and one abnormal X chromosome; they usually have milder disease which has later onset than hemizygous males. However, a number of studies have demonstrated a significant burden of disease in females. Indeed, all the manifestations described in males may also occur in females, though typically the disease has a later onset, slower progression and milder clinico-pathological changes.
The underlying mechanism whereby heterozygous females develop symptoms is unknown – most have almost normal levels of circulating enzyme and the random process of X chromosome inactivation means their tissues should be a mosaic of normal and deficient cells.


OMIM single geneFabry
Kegg PathwayAGAL

The gene GLA encode for the Alpha-galactosidase, a glycoside hydrolase enzyme that hydrolyses the terminal alpha-galactosyl moieties from glycolipids and glycoproteins. This enzyme is a homodimeric glycoprotein that hydrolyses the terminal alpha-galactosyl moieties from glycolipids and glycoproteins. It predominantly hydrolyzes ceramide trihexoside, and it can catalyze the hydrolysis of melibiose into galactose and glucose. Like all enzymes destined for the lysosomes the α-galactosidase A protein is co-translationally modified with mannose-6-phosphate residues. A portion of the phosphorylated enzyme is actually secreted from cells and then taken up by receptor-mediated endocytosis via mannose-6-phosphate receptors on the plasma membrane of cells. This secretion and re-uptake of α-galactosidase A provides the basis for the rationale behind enzyme replacement therapy

A variety of mutations in this gene affect the synthesis, processing, and stability of this enzyme, which causes Fabry disease, that results from a failure to catabolize alpha-D-galactosyl glycolipid moieties.

Figure 1. Galactose metabolism

D-Galactose is a constituent of oligosaccharides and is produced by hydrolysis of Melibiose, Raffinose, Stachyose, Allolactose, Glycerol 1-alpha-D-galactoside, Melibitol, and Galactinol by Galactosidase, alpha (AGAL,, or by hydrolysis of Lactose by Lactase ( LPH ). Alpha-(D)-Galactose 1-phosphate if formed by transfer of the phosphate moiety from ATP to D-Galactose catalyzed by Galactokinase 2 ( GALK2 ) and Galactokinase 1 ( GALK1 ).
Subsequent transformation of the alpha-(D)-Galactose 1-phosphate to alpha-D-Glucose 1-phosphate and UDP-D-galactose is catalyzed by Galactose-1-phosphate uridylyltransferase ( GALT ). Both products participate in the further transformations. Phosphoglucomutase 1 ( PGMU ) then catalyzes formation of the alpha-(D)-Glucose-6-phosphate from alpha-D-Glucose 1-phosphate. UDP-D-galactose is transformed further in the two subsequent reactions. In the first reaction the formation of Lactose by group of enzymes occurred: UDP-Gal:betaGlcNAc beta 1,4- galactosyltransferase, polypeptide 1 ( Lactose synthase) and by UDP-Gal:betaGlcNAc beta 1,4- galactosyltransferase, polypeptide 2 ( B4GT2 ). In the second reaction UDP-D-galactose is transformed to UDP-D-glucose by UDP-galactose-4-epimerase ( GALE ). UDP-D-glucose participates in formation of Glycogen catalyzed by two enzymes, glycogen synthase 2 (liver) ( GYS2 ) and by glycogen synthase 1 (muscle) ( GYS1 ). Glycogen is the substrate of one more reaction of formation alpha-D-Glucose 1-phosphate catalyzed by Glycogen phosphorylase. Apha-D-Glucose 6-phosphate also participates in glycolysis and gluconeogenesis. Hydrolysis of Apha-D-Glucose 6-phosphate to D-Glucose is catalyzed by Glucose-6-phosphatase, catalytic subunit ( G6PT ). This reaction can proceed also in the opposite direction under catalysis of other enzymes, Hexokinase 1 ( HXK1 ), Hexokinase-2 ( HXK2 ), Hexokinase 3 (white cell) ( HXK3 ) and Glucokinase (hexokinase 4) ( HXK4 ).

Additional Info on phospholipids metabolism and galactose metabolism (Cartoon)


Figure 2. Three-dimensional model of Alpha-Galactosidase

Lysosomal-alpha-galactosidase A is a relatively heat-labile, homodimeric glycoprotein consisting of 2 identical 49-kDa subunits. The enzyme exists in several forms, which differ in the amount of sialic acid in the carbohydrate chains. Activity is easily measured with the use of such synthetic substrates as 4-methylumbelliferyl-alpha-D-galactopyranoside; optimum pH is 4.6.
As said above, the GLA gene is located at Xq22 on the long arm of the X chromosome. It is approximately 12 kb and contains 7 exons that are associated with extensive 5’ regulatory and 3’ flanking sequences. The processed message is 1.45 kb and encodes a 50-kDa precursor polypeptide of 429 amino acids. The primary polypeptide gene product undergoes cotranslational glycosylation in the endoplasmic reticulum, with downstream trimming of the polypeptide and modification of theoligosaccharide (including 6-O phosphorylation of mannose residues) required for localization in lysosomes. A proportion of the phosphorylated enzyme is secreted from the cell and is taken up by receptor-mediated endocytosis through mannose-6-phosphate receptors in the plasma membrane (Figure 3). The secretion and reuptake of alpha-galactosidase A provides the rationale for enzyme replacement therapy (ERT).

Figure 3. Sequence of events in the biosynthesis and trafficking of alpha-galactosidase A


Protein aminoacid percentage calculation


The pathogenesis of Fabry disease is not well understood. It is attractive to assume that the clinical manifestations are the direct result of accumulation of of neutral glycosphingolipids, especially globotriaosylceramide (Gb3), within a range of cell types and tissues, leading to disturbed cell/organ function, but this explanation is likely to be simplistic. It is well recognized that tissue damage in Gaucher disease, the commonest lysosomal disorder, results from inflammation, cytokine release from macrophages engorged with storage material and abnormal intra- and inter-cellular signalling. These processes, triggered by the presence of excessive tissue Gb3 storage, are likely to be equally important in Fabry disease. The absence of infantile manifestations of Fabry disease despite deficient α-galactosidase A and Gb3-accumulation supports the hypothesis that Gb3 is not solely responsible for disease manifestation. However,different hypothesys have been postulated about the mechanism by which Gb3 can contributed to cellular/tissue damage in Fabry disease:
1. Valbuena et al. hypothesized that the overloading of lysosomes with Gb3 may simply lead to the rupture of cytoplasma and in consequence to cell death (Valbuena et al, 2008);
2. Secondary effects of Gb3 accumulation which might be responsible for disease pathology include also inflammatory processes. Recently, Gb3 has been shown to be identical with membranous CD77 (Thomaidis et al, 2009) which is supposed to play an important role in apoptosis and necrosis . In addition, Rozenfeld and co-workers reported perturbed leukocyte function in Fabry disease compared to healthy controls and abnormal numbers of different immune cells, including lymphocytes, monocytes, CD8+ cells, B cells and dendritic cells (Rozenfeld et al, 2009);
3. Finally, Gb3-accumulation has been reported to induce oxidative stress and/or the formation reactive oxygen species (ROS) (Shen et al., 2008). Lipids and proteins may be oxidised and may be unable to function. Of note, ERT increased the generation of ROS in vitro, and up-regulated the intracellular adhesion molecule ICAM 1. It was hypothetized that ERT may enhance endothelial damage, allowing to understand continuously occurring strokes in patients on treatment.
4. Another gateway into alteration of endothelial function may be given by the Nitric-Oxide-Synthase-3-genotypes. Endothelium-derived nitric oxide is a key regulator of vessel wall function and cardiovascular homeostasis. A genetic variant of the Nitric-Oxide-Synthase-3-gene is suspected to disturb this homeostasis and has been found to be associated with a decreased thickness of the posterior wall of the left ventricle (Rohard, 2008). This observation may in part explain the large variability of cardiac phenotypes in Fabry disease.

It is intriguing that heterozygous females have detectable—indeed, sometimes even normal— circulating levels of enzyme, and yet are usually affected by organ damage. Uptake and intracellular localization of the enzyme within lysosomes of diverse cells of different tissues is likely to be very important.
A mouse model of Fabry disease has now been developed, and may yield clues regarding the pathogenesis.

Anderson-Fabry Disease: Extrarenal, Neurologic Manifestation

Disease mechanism: Fabry disease, 2009

Figure 4. Mechanism of Fabry disease

PATHOGENESIS OF THE VASCULOPATHY- "The Swollen Endothelial Cells Hypothesis"

The major clinical manifestations of the disease, such as stroke, cardiac dysfunction, and renal impairment, are thought to be caused by vasculopathy due to progressive accumulation of globotriaosylceramide in vascular endothelium and smooth muscle cells. The pathogenesis of the vasculopathy has not been elucidated.
Historically, it has been thought that accumulation of lipid in the endothelium of capillaries and other small vessels resulted in infarction and ischemia leading to tissue damage. However, more recent studies have indicated that endothelial dysfunction plays a significant role in the pathenogenesis of this disease. In particular, swollen endothelial cells (ECs) due to lysosomal deposition of Gb3 are currently thought to play a role in ischemic vascular events. Altarescu and co-workers demonstrated significant blunting of endothelial response to acetylcholine stimulation resulting in significant changes in blood flow in Fabry patients. In addition, DeGraba et al. have demonstrated an increase in markers of endothelial activation in plasma of patients with this disease, resulting in a proinflammatory state.
Microvessel ECs are of particular interest in the pathology of Fabry disease. One of the diagnostic hallmarks of this disease is the presence of angiokeratomas which consist of tangles of dilated and thrombic small vessels containing lipid-laden endothelium indicating that microvessels of the skin are one of the primary sites of disease involvement. Global expression profiling of endothelial cells from large and small vessels from different anatomic sites has indicated that, in addition to the general expression of genes specific to all cells of endothelial origin, microvessel ECs differentially express genes involved in interactions with circulating blood cells and responses to pathogens. These interactions contribute to inflammatory reactions. Of particular interest, Chi and co-workers found that microvascular endothelial cells express receptors for a variety of paracrine signals from neuroglial cells, suggesting close interaction between microvessel ECs and peripheral nerves. Nearly all Fabry patients suffer from neuropathic pain in their hands and feet which can debilitating. Closer investigation of the interaction of microvessel ECs with neuronal cell types may be useful in understanding the origin of this pain. In fact, the relationship between abnormal glycosphingolipid metabolism and the vascular disease remains unclear.

Establishment and Characterization of Fabry Disease Endothelial Cells with an Extended Lifespan, 2007


Neutral glycosphingolipids are mainly synthesized in the liver cells and are released into circulation incorporated into lipoproteins. In addiction, senescent erythrocytes membranes break-up contributes to increase the serum level of circulating glycosphingolipids. The mode of systemic accumulation of neutral glycosphingolipids and their particular electivity for endothelial cells and smooth muscle, are the peculiar characteristic of AFD compared to other sphingolipidosis, but The mechanism by which this accumulation causes symptoms of disease is still unknown. Accumulation of glycosphingolipids in not vascularized sites such as the cornea and neural cells, which are protected by the blood-brain barrier, is explained by the fact that glycosphingolipids with terminal alpha-galactosides have an intracellular synthesis. The glycosphingolipids more represented as material of accumulation are globotriaoilceramide (Gb3) and galabiosilceramide. Under physiological conditions the galactosidase A leads to the enzymatic splitting of Gb3 in lactosilceramide that is totally removed by the reticuloendothelial system. The lack of specific enzyme activity involves the gradual and constant accumulation of Gb3 in all cells, histologically documented even before clinical symptoms appear as organ damage typical of AFD. The particular severity of renal histological lesions compared to other organs is attributable both to higher concentrations in renal cell precursor of Gb3, and to the fact that in the kidney is specifically present the enzymatic activity of galactosyltransferase, involved in the synthesis of galabiosilceramide, which is totally absent in other organs such as the liver, spleen, lungs, brain, to justify the minor accumulation of damage in their structures.
The formation of abnormal intracellular deposits of glycosphingolipids is mainly mediated by the ability of tissues to uptake, by specific membrane receptors, circulating plasma Gb3 incorporated into lipoproteins HDL and LDL, and with blood concentrations significantly higher than individuals with normal alpha-galactosidase A enzymatic activity. Two additional glycosphingolipids present in intracellular stores of patients with AFD have been identified in erythrocyte antigens of blood groups B and B1. Therefore, while patients of blood group A and O only accumulate Gb3 and galabiosilceramide, the subjects of group AB and B accumulate four substrates of glycosphingolipids, however, this difference in erythrocyte antigens does not differ substantially phenotypic of AFD.

Figure 5. Enzymes deficiency in Fabry and Gaucher disease


The pathological abnormalities can be divided into disease-specific and secondary changes that are not disease-specific but reflect organ abnormalities and dysfunction. The most visually striking and historically important are lysosomal inclusions or lipid deposits that are seen in almost all cell types. They are prominent in vascular cells, both endothelial and smooth muscle cells, cardiac cells including endocardial cells, cardiomyocytes and cardiac valves, kidney epithelial cells (tubular and glomerular cells and podocytes) and nerve cells including dorsal root ganglia and some central nervous system neurons. Abnormal reactivity of endothelial cells with changes in blood flow in the brain and in peripheral vessels has been documented on magnetic resonance imaging (MRI), positron emission tomography (PET), transcranial Doppler imaging (TCD), and plethysmography.
The secondary pathological changes are organ-specific but not necessarily disease-specific. Blood vessels may be thickened with a rather characteristic arteriosclerotic change that is different from typical atherosclerosis plaque. True cardiac hypertrophy is often present with secondary fibrosis, and valves are often thickened. The renal glomeruli undergo progressive change that starts with mesangial widening, followed by focal fibrosis ending with a completely fibrotic and obsolescent glomerulus. Tubular and interstitial fibrosis occurs as well. The brain may have rarefied and gliotic lesions secondary to ischemia, but spontaneous neuronal death and cerebral cortical atrophy have not been described . Decreased levels of thrombomodulin ™ and increased plasminogen activator inhibitor (PAI) were found in Fabry disease patients thus suggesting that a prothrombotic state may be one cause of stroke in these patients. The precise cause of increased incidence of stroke is not established. Findings that could contribute to this increased risk include abnormal nitric oxide and non-nitric oxide dependent endothelial dilation and abnormal endothelial nitric oxide synthase (eNOS) activity leading to aberrant vascular functioning. Paradoxical hyperperfusion is seen in strokelike lesions whose significance is not known.
Nonischemic compressive complications of dolichoectatic intracranial arteries include hydrocephalus, optic atrophy, trigeminal neuralgia, and cranial nerve palsies.


The clinical onset usually occurs in childhood, although sometimes the first symptoms of the disease can appear in the second or third decade of life.


The first clinical manifestations of the disease, which consist of episodes of severe pain in the extremities (acroparesthesias), hypohidrosis, corneal and lenticular changes, and skin lesions (angiokeratoma) develop in childhood.
There are 3 distinct clinical entities.

1. Male homozygotes with classical manifestation
No alpha-galactosidase activity in plasma.
• Onset in childhood or early adolescence. Often patients have slight builds with characteristic coarse facial features and delayed puberty.
• Early symptoms of burning pain and paraesthesia in the extremities (acroparaesthesia) are a major cause of morbidity. Painful crises may be triggered by temperature change, fever, sun, physical exertion etc.General fatigue and weakness is common.
• Progressive development of symptoms consistent with disease affecting many different systems. For example:
- Skin.Angiokeratomas occur early and are small punctate red to blue-black telangiectasiae typically in a 'bathing suit' distribution. Hypohydrosis. Lymphoedema in lower extremities.
- Eye. Lens, cornea, conjunctiva and retina may all be involved. Particular types of pathognomic lens opacity have been described (the propeller or wedge shaped opacity and the Fabry cataract).
- Cardiovascular system. Problems typically develop in the fourth decade.This can produce anginal pain in adulthood with varied complications ranging from arrhythmias to myocardial infarction and heart failure.3
- Cerebrovascular disease. This can produce problems ranging from personality change and psychosis to varied manifestations of multifocal cerebrovascular disease. It typically develops in the fourth decade.
- Gastrointestinal disease. This can include symptoms of diarrhoea, weight loss abdominal pain, nausea and vomiting.
- Renal disease. This produces hypertension, proteinuria and progressive renal failure. Such symptoms typically develop in the second and third decade.
- Other organs and systems. Widespread involvement produces many other manifestations of the disease including cough, breathlessness, wheeze etc.

2. Male homozygotes with atypical manifestation.
Some alpha-galactosidase activity in plasma (5-35%). Probably the most common variant.
• Often asymptomatic
• Adult onset
• Present late, often sixth to eighth decade
• Usually present with cardiac involvement including cardiomegaly, mitral insufficiency, cardiomyopathy
• Can present with proteinuria
• Occasionally develop acroparaesthesia

3. Female heterozygotes
Variable (0-100%) plasma alpha galactosidase activity depending on random X-chromosomal activation.
• Variable presentation
• Adult onset
• Dystrophy of cornea in the subepithelial layer with whorled streaks in 70%
• Angiokeratomas in 30%
• Rarely hypohidrosis and other organ involvement (Renal failure less than 1%).



• burning paroxysmal pain crises to hands palms and feet soles (acroparesthesia) to recede in intensity and frequency with age.
• fever and increase in VES.
• visceral neuropathic symptoms.
• Intolerance to heat and to increases in ambient temperature, due to the skin hypohidrosis.
• skin teleangiectasias in the back headset or other regions.
A 14-year-old Boy with Pain in Hands and Feet,2009

Youth age:

• mainly the presence of cutaneous angiokeratomas with a "swimming costume" distribution.
• ipohidrosis or anhidrosis, leading to collapse from heat or strenuous exercise.
• occasionally persistent proteinuria and isolated effect of an early renal damage, secondary to glomerular disease.
• impaired ability to concentrate urine, secondary to tubule-interstitial disease.
• “cornea verticillata", pathognomonic of corneal dystrophy from sfingolipids accumulation in epithelial cells.


• gradual and progressive deterioration of renal function to terminal chronic uremia within 40 years of age in male patients.
• cardiovascular and / or cerebrovascular serious clinical complications (leading cause of death of patients with MAF).
• The progression of cardiac disease is manifested by:
- early coronary artery disease
- Left ventricular hypertrophy by accumulation,
- very frequent valvulopathy with mitral prolapse,
- arrhythmias secondary to the progressive damage of the conduction system (paroxysmal atrial fibrillation, atrioventricular block of Wenckebach-Luciani,syndrome Wolff-Parkinson-White, shorter PR range).
• Neurological clinical manifestations are due to multifocal impairment of cerebral microcirculation and are represented by:
- Transient ischemic attacks (TIA),
- tonic-clonic seizures,
- ischemic or hemorrhagic stroke,
- parkinsonism.


The mechanism by which neutral Neutral glycosphingolipids accumulation causes symptoms of disease is still unknown.
The clinical manifestations of Fabry disease begin in childhood or adolescence. Classic symptoms include pain and parathesis in the extremities, gastrointestinal disturbances, cardiomyopathy, progressive renal impairment, corneal and lenticular opacities and characteristic skin lesions called angiokeratomata. These symptoms are all due to the deposition of neutral glycosphingolipids, especially
globotriaosylceramide (Gb3), in the walls of small vessels, kidney tubule and glomeular cells, nerves and dorsal root ganglia. The characteristic skin lesions of Fabry disease are the earliest signs that may lead to diagnosis in childhood. Death usually occurs in early adulthood from renal and cardiac complications of the vascular disease. Carrier females are usually asymptomatic but can, in rare cases, be as severely affected as hemizygous males. The most consistent clinical phenotype found in carrier females is corneal opacity.

Symptoms: Narrative review: Fabry disease, 2007



cornea verticillata , corneal dystrophy due to glycosphingolipids deposits dependents of corneal epithelial cells. The corneal opacity color varies from white to golden-brown, initially at headquarters to gradually extend to the periphery.
• on fundus oculi changes in the retinal vessels, due to sfingolipids deposits in endothelial cells.
• conjunctival vascular lesions.
Fabry's cataract, lenticular opacities due to linear deposits of translucent material near the rear capsule of the crystalline lens.

Figure 6. Characteristic cornea verticillata in Fabry disease

Skin and mucous membrane:

Angiokeratomas : clusters of superficial or slightly detected angiomatous lesions on the skin with dark bluish red color, with possible modest cutaneous hyperkeratosis. It tend to increase progressively over time both in size and number assuming a "swimming costume" distribution for symmetrical involvement of trunk, perineum, scrotum, penis and vulva.
• teleangiectasias also in conjunctiva and oral cavity.
• anhidrosis od ipoanhidrosis, due to sfingolipidic infiltration of sweat glands. This leads to intolerance to heat, to sudden elevation in ambient temperature, until the "heat stroke" due to prolonged physical activity or higher temperature.

Figure 7. Angiokeratoma

Kidneys :

• Ultrasound examination shows increased size due to progressive glycosphingolipids accumulation.
• Renal biopsy shows hypertrophic and visibly vacuoles renal cell due to the presence of intracytoplasmic lipid material.
• isolated proteinuria without deterioration of urinary sediment is an early sign of renal involvement.
• progressive individual cells involvement with progression to glomerular focal and segmental sclerosis up to global sclerosis.
• isosthenuria ed iposthenuria for impaired ability to concentrate urine.
• involvement of the proximal tubule's epithelial cells with Fanconi syndrome (aminoaciduria, tubular acidosis, normoglycemic glycosuria).
• progressive deterioration of anatomical structures with deteriorating renal function till chronic terminal uremia in the third, fourth, fifth decade of life.

Figure 8. Histopathologic changes in the kidney

Heart and vessels:

• multiple heart disease due to progressive Gb3 accumulation in heart muscle cells, in valvular fibrocells, in the conduction tissue, in coronary vascular endothelium.
hypertrophy and left ventricular overload.
• normal systolic function and preserved for a long time.
• diastolic deficit, one of the most common causes of stress dyspnea.
• shorter PR range.
• cardiac arrhythmias also in young age.
• cardiac valvular abnormalities with mitral valve insufficiency in 60% of cases.
• myocardial ischemia, cardiac strok and diffuse coronary artery disease are leading causes of death.

Cardiac manifestations of Anderson-Fabry disease in children and adolescents,2008

Nervous system:

• acroparesthesias: paroxysmal painful crisis to the ends.
ischemic stroke and ischemic attacks, one of the leading causes of exitus
• cerebral vasculopathy worsened by the coexistence of hypertension and chronic renal failure in dialysis treatment replacement, and severe cardiac involvement.
• Sometimes progressive deterioration of cognitive functions.

Central nervous system involvement in Anderson-Fabry disease: a clinical and MRI retrospective study,2008

Depression in adults with Fabry disease: a common and under-diagnosed problem,2007

Figure 9. MRI features of Fabry disease

Gastrointestinal involvement:

• abdominal pain with alternating constipation and diarrhea.
• presence of glycosphingolipids deposits in the plexus of Meissner's cells, as well as in intestinal vessels endothelial cells .
• abdominal colic

Growth retardation:

with characteristics craniofacial and oral abnormalities like prognathism and maxillar sinus cysts, till to the characteristic "facies acromegalica".

Osteo-articular pathology:

deflection of distal interphalangeal joints with partial functional impotence.


There is a big list of possible differential diagnoses according to the varied clinical presentations. Correct diagnosis is important because of the progressive morbidity associated with advancing disease. Early diagnosis is now important because some disease manifestations (Fabry cardiomyopathy) can be modified with enzyme replacement therapy.

Diagnosis is based on:

• Biochemical diagnosis obtained with the determination of leukocyte's alpha-galactosidase A activity: it is absent or greatly reduced in males, while in females the activity is often normal or only slightly reduced.
• Family history: because Fabry disease is an X-linked disorder and most cases result from inherited mutations rather than new mutations, most patients have blood relatives who are either affected males or carrier females. Identification of affected males is relatively easy, by using a combination of pedigree analysis and measurement of alpha-galactosidase A activity in plasma or leukocytes. The identification of carrier females is more difficult because many have normal levels of alpha -galactosidase A.
• The presence of the characteristic “cornea verticillata” which, due to the high frequency both in males than in females, it is an important diagnostic aid.
• The demonstration of increased concentrations of Gb3 in urine sediment is highly suggestive of the diagnosis.
• Detection of "cross of Malta" lipid (birefringent lipid molecules). finds in the urinary sediment, examined with an optical microscope with polarized light.
• Diagnosis confirmation is obtained through genetic analysis. Confirmation of diagnosis is by demonstration of absent or deficient levels of alpha-galactosidase A in leucocytes, plasma or cultured fibroblasts.

Taking pedigrees of newly diagnosed patients is worthwhile and may reveal more affected individuals.

Prenatal diagnosis
is possible by detecting deficient enzyme activity (alpha-galactosidase activity can be measured from chorionic villus biopsy in the first trimester or cultured amniotic cells in the second trimester) or by detecting specific mutations in chorionic villi. Heterozygote female fetuses can be identified if the family mutation is known.
Other helpful investigations include ECG, MRI, echocardiography etc. Also in this case, eye examination may show diagnostic corneal or lenticular deposits.

Differential diagnosis


The primary risk factor for Fabry disease is having family members with the disease or who are carriers of the disease.


I. Enzyme Replacement Therapy (ERT)

The most important advance in the treatment for Fabry disease has been the introduction of Enzyme Replacement Therapy (ERT). Two products have been developed: agalsidase alfa and agalsidase -galactosidase A that are produced in beta (agalsidase alfa). Both are versions of human genetically engineered cell lines by different techniques. The primary amino acid sequences of the gene products are the same; however, the structures of the oligosaccharide side chains are different. Compared with agalsidase alfa, agalsidase beta contains a higher proportion of the mannose-6-phosphate residues that are required for cellular uptake of exogenously administered enzyme and is taken up more readily by cultured skin fibroblasts.. Only agalsidase beta is approved for treatment for Fabry disease in the United States, although both agents are approved for clinical use in other countries. Enzyme replacement therapy with either drug is very expensive, costing approximately $250 000 per year for the average adult with the disease.
Randomized, placebo-controlled, clinical trials and longer-term, open-label extension studies of both products have demonstrated that the enzyme effectively cleared the accumulated glycolipid from key cells in the kidney, as well as from cells in the skin and heart. Additional studies showed that enzyme replacement therapy stabilized renal function, improved cardiac function, and quality of life. In April, 2003 the FDA approved Fabrazyme (agalsidase beta) for treatment of Fabry disease.
Recently, a panel of physicians expert in Fabry disease recommended that enzyme replacement therapy be initiated in all patients with Fabry disease as soon as possible – ideally, as soon as clinical signs and symptoms such as pain or isosthenuria are observed. Although enzyme replacement therapy has not yet been evaluated in children with Fabry disease, experience in type 1 Gaucher disease has indicated that enzyme replacement infusions are well tolerated by young children. Carrier females with significant disease manifestations should also be treated with enzyme replacement therapy. Also, there are no currently published studies of enzyme replacement therapy in Fabry patients who are undergoing dialysis or have received a kidney transplant; however, because such patients are at high risk for cardiac, cerebrovascular, and neurological complications such as transient ischemic attacks and stroke, enzyme replacement therapy in this population is also recommended.

Long-Term Effects of Enzyme Replacement Therapy on Fabry Cardiomyopathy, 2009

Advances in the management of Anderson- Fabry disease: enzyme replacement therapy,2002

Effects of enzyme replacement therapy in patients with Anderson-Fabry disease: a prospective long term cardiac magnetic resonance imaging study,2009

Enzyme replacement therapy for Anderson-Fabry disease, 2010

II. Enzyme Enhancement (Chaperone) Therapy

Many investigators have shown that some mutations in GLA genes result in destabilization, aggregation, and premature degradation of a mutant enzyme polypeptide that is catalytically active. Strategies directed at preventing premature degradation by pharmacologic stabilizing of the mutant protein have been shown to substantially increase residual alpha-galactosidase A activity. Because the level of enzyme activity necessary to prevent disease is relatively low (< 10%), even a modest increase in chaperone-induced enzyme activity might be expected to arrest the progression of Fabry disease. Chaperone therapy is still being investigated and is not available for clinical use.

Pharmacological chaperone therapy by active-site-specific chaperones in Fabry disease: in vitro and preclinical studies, 2009

III. Gene Therapy

Despite the effectiveness of enzyme replacement therapy, treatment will probably be future genetic. Now it still remains a distant hope: even if we know the gene sequence of every absent or lacking protein which cause individual hereditary disorders, one of the major problems of gene therapy is the search for suitable carriers for intracellular transport of a copy of the defective gene.

Lentiviral vectors for immune cells targeting, 2010

Non-viral nanovectors for gene delivery: factors that govern successful therapeutics, 2010

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