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Fabry disease …
- Updated 05.24.2024
- Released 07.05.1994
- Expires For CME 05.24.2027
Fabry disease
Introduction
Overview
Fabry disease is an X-linked disorder of glycosphingolipid metabolism caused by a deficiency of alpha-galactosidase A. As a result, patients have a markedly increased risk of developing common-looking small-fiber peripheral neuropathy, ischemic stroke, myriad cardiac manifestations, and chronic renal disease. Some studies have found that about 0.5% of patients with stroke have GLA gene mutations. Specific therapy for Fabry disease now exists, including enzyme replacement and pharmacological chaperones. Modified enzyme replacement therapy with a long circulation half-life and substrate synthesis inhibitors is being tested. Current enzyme replacement therapy does not lower the risk of stroke. Clinical experience suggests that antiplatelet agents that are ADP-receptor blockers markedly reduce the risk of stroke in Fabry disease patients.
Key points
• Fabry disease is a genetic risk factor for stroke, small fiber neuropathy, heart, and kidney disease. | |
• It is X-linked, but heterozygote women may be symptomatic too. | |
• Fabry disease may explain approximately 0.13% of all strokes. | |
• The main complications of Fabry disease are nonspecific in character and, therefore, the disease is likely to be overlooked. | |
• Therapy includes specific intervention, such as enzyme replacement, and pharmacological chaperones. | |
• Current enzyme replacement therapy for Fabry disease, if initiated in adulthood, does not lower the risk of stroke and may not reduce the risk of cardiac death. |
Historical note and terminology
In 1898, German dermatologist Johannes Fabry (1860–1930) and English surgeon William Anderson (1842–1900) independently described the dermatological features of patients with what is now known as angiokeratoma corporis diffusum (56; 05).
Fabry reported skin lesions in a 13-year-old boy that initially were thought to represent purpura nodularis. After further study of this patient, the lesions were found to contain small-vessel aneurysms. Fabry classified this disease as “angiokeratoma corporis diffusum” (56). Fabry reported a follow-up on his original patient in 1916.
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Watercolor of the histology of an angiokeratoma, from Fabry's original article (1898)
"Hematoxylin staining. Cutis papillae dark blue, almost violet, epidermis light blue, blood foci greenish-yellow, section through a larger nodule, near the blood papules the epidermal papillae are elongated. Some blood dropped ...
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Watercolor of skin histology, using a carmine stain, from Fabry's original article (1898)
"Carmine coloring. Horny part of the epidermis. Epidermis dark red, dermis and subcutaneous connective tissue light red. An elongated, single-chamber hemorrhage in the cutis, apparently near a sebaceous duct, to the left of whi...
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Watercolor of skin histology, using Weigert fibrin staining, from Fabry's original article (1898)
"Weigert fibrin staining. The incision has struck some hemorrhages of the dermis, also quite close to the epidermis; the contrast between blue fabric and brown colored blur is very striking; the section shows no tissue hypertro...
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Watercolor of skin histology, using a carmine stain, from Fabry's original article (1898)
"Carmine staining. A comparatively large hemorrhage only in the epithelial part of the skin. tissue red, bleeding brown; part of the blood has fallen out, as is usually the case; the degree of secondary hypertrophy can be clear...
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Watercolor of the histology of a hemorrhagic papule, using H&E staining, from Fabry's original article (1898)
"Hematoxylin and eosin staining. Here is a unicameral small and tapered hemorrhagic papule." (Source: Fabry J. Ein Beitrag zur Kenntniss der Purpura haemorrhagica nodularis [Purpura papulosa haemorrhagica Hebrae]. Archiv für De...
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Watercolor of the histology of a subcutaneous hemorrhage, using Taenzer's orcein staining, from Fabry's original article (1898)
"Hemorrhage in the area of a fat lobe in the subcutis; the blood here clearly contrasts with the tissue; the preparation shows that the bleeding is confined within one acinus and does not spread to neighboring ones." (Source: F...
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Watercolor of the histology of venous congestion, using Taenzer's orcein staining, from Fabry's original article (1898)
"Taenzer's orcein staining shows a dilated vein due to blood congestion." (Source: Fabry J. Ein Beitrag zur Kenntniss der Purpura haemorrhagica nodularis [Purpura papulosa haemorrhagica Hebrae]. Archiv für Dermatologie und Syph...
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Watercolor of the histology of vascular congestion, using carmine staining, from Fabry's original article (1898)
"Carmine staining shows a club-shaped, distended small artery due to congestion." (Source: Fabry J. Ein Beitrag zur Kenntniss der Purpura haemorrhagica nodularis [Purpura papulosa haemorrhagica Hebrae]. Archiv für Dermatologie ...
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Angiokeratomas in Fabry disease, from Fabry's original article (1898)
Photograph of patient Emil Honke at the age of 13 years. (Source: Fabry J. Ein Beitrag zur Kenntniss der Purpura haemorrhagica nodularis [Purpura papulosa haemorrhagica Hebrae]. Archiv für Dermatologie und Syphilis 1898;43:187-...
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Angiokeratomas in Fabry disease, from Fabry's follow-up article (1916) on his original case
Photograph of patient Emil Honke in 1915 at the age of 30 years. (Source: Fabry J. Zur Klinik und Ätiologie des Angiokeratoma. Archiv für dermatologische Forschung 1916;123[2]:294-307. Photograph restored by Dr. Douglas J Lansk...
Anderson also diagnosed similar skin lesions in a 39-year-old male as angiokeratoma (05). This patient had albuminuria in addition to other clinical features that Anderson argued might be due to a systemic process rather than a disease limited to the skin. In 2016, Gaggl and colleagues published an extended pedigree in which Anderson's original case was the propositus; the pedigree spans seven generations and includes six affected males and seven obligate female carriers (61). The pedigree is consistent with an X-linked recessive trait.
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Section of angiectasis (vascular ectasia), from Anderson's original article (1898)
"1, stratum corneum of epidermis; 2, stratum Malpighi; 3, papillary layer of dermis; 4, angiectasis, occupied by coagula and blood-corpuscles; 5, angiectasis, with dissepiment (ie, a partition in a part or organ; a septum); 6, ...
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Pedigree of the patient with Fabry disease reported by Anderson (1898)
The pedigree spans seven generations and includes six affected males and seven obligate female carriers. Symbols: circle, female; square, male; dotted circle, obligate female carrier; filled square, diseased male; arrow, propos...
The disease remained under the purview of dermatologists until 1947, when Pompen and colleagues described the first postmortem pathological examination on two affected brothers. This report documented the existence of abnormal storage vacuoles in blood vessels throughout the body and established that Fabry disease was a generalized storage disorder (119).
Various studies in the 1960s documented pedigrees consistent with an X-linked recessive inheritance pattern, most notably a study from the University of Wisconsin by German-American medical geneticist John M Opitz (b 1935) and colleagues (35; 175; 39; 112; 93).
Sweeley and Klionsky first elucidated the biochemical nature of the storage material in Fabry disease (157). They determined that the accumulating substance consisted primarily of two glycosphingolipids, globotriaosylceramide and galabiosylceramide. Brady and colleagues showed that Fabry disease was caused by a deficiency of the enzyme alpha-galactosidase A, resulting in the storage of glycolipids containing a terminal alpha-galactosyl residue such as globotriaosylceramide (18).
The molecular structure of the gene encoding alpha-galactosidase A, GLA, was first identified as the full-length cDNA clone in 1986 (14), and the entire gene organization was determined in 1989 (89).
Following the development of enzyme replacement therapy for Gaucher disease, the production of glucocerebrosidase and the mechanisms of lysosomal targeting were used as a blueprint to produce recombinant human alpha-galactosidase, which received regulatory approval from the European Union in 2002 and FDA approval in 2003.
Clinical manifestations
Presentation and course
Patients with Fabry disease are typically divided into a severe, classic phenotype, which is caused by mutations that are associated with no (or less than 3%) residual alpha-galactosidase A activity and a generally milder nonclassical phenotype with variant, atypical, or late-onset mutations associated with definite residual activity of up to 30% of mean normal values (153; 06).
In affected hemizygous males with the classic phenotype, clinical symptoms usually begin in late childhood or adolescence with the development of neuropathic pain in the extremities (acroparesthesia), poor heat and exercise tolerance, angiokeratoma, hypohidrosis, corneal and lenticular opacities (cornea verticillata), and psychosocial problems (127). Because of the storage of glycolipid in the vascular system, progressive cardiac, renal, and cerebral involvement follows, mostly during the second to fourth decades. Late complications of the disease include deafness and tinnitus, stroke, cardiac conduction disturbances, hypertrophic cardiomyopathy with left ventricular hypertrophy, valvular heart disease, gastrointestinal problems, and chronic renal failure.
Nonclassical Fabry disease is characterized by a more variable disease course, in which patients are generally less severely affected, disease onset is delayed, and disease manifestations may be limited to a single organ (06; 32). Patients with Fabry disease identified in screening studies of individuals with stroke, renal failure, or cardiomyopathy often have the nonclassical phenotype (06).
Despite the X-linked inheritance pattern of Fabry disease, women often have signs and symptoms of Fabry disease due to skewed X chromosome inactivation, although they are usually less severely affected than men (96; 48; 06).
Clinical features of Fabry disease in 20 children (13 boys and seven girls) were reported in a Russian study, unfortunately without indication of the frequencies separately for boys and girls; in descending order of frequency were acroparestheia, proteinuria, angiokeratomas, hypohidrosis, gastrointestinal features (abdominal pain or discomfort, diarrhea), keratopathy, cardiac features (left ventricular hypertrophy, chest pain), and hearing loss (136). Another common early sign of Fabry disease in both boys and girls is low skeletal muscle mass (94).
Dermatologic findings. Angiokeratomas consist of clusters of individual ectatic blood vessels covered by a few layers of skin. These lesions are flat or slightly raised, dark red to blue in color, and are usually located in the groin, buttocks, upper legs, and umbilical regions. The angiokeratomas become apparent in childhood and gradually increase in size and number over the years. Angiectasias may also occur in the oral mucosa, pinna of the ear, conjunctiva, and retina.
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Angiokeratoma: multiple small pink to dark-red spots on the lateral trunk
(Source: Ezgu F, Alpsoy E, Bicik Bahcebasi Z, et al. Expert opinion on the recognition, diagnosis and management of children and adults with Fabry disease: a multidisciplinary Turkey perspective. Orphanet J Rare Dis 2022;17[1]:...
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Red-purple, nonblanching vascular skin lesions (angiokeratoma) on the umbilicus of a patient with Fabry disease
Angiokeratoma are usually distributed on the buttocks, groin, umbilicus, upper thighs (bathing trunk distribution), and, occasionally, on the lips and oral mucosa. (Source: Burlina AP, Sims KB, Politei JM, et al. Early diagnosi...
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Angiokeratoma: multiple 1- to 5-mm pink to dark-red or blue-black spots with hyperkeratotic surface on the scrotum
(Source: Ezgu F, Alpsoy E, Bicik Bahcebasi Z, et al. Expert opinion on the recognition, diagnosis and management of children and adults with Fabry disease: a multidisciplinary Turkey perspective. Orphanet J Rare Dis 2022;17[1]:...
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Red-purple, nonblanching vascular skin lesions (angiokeratoma) on the lips and oral mucosa of a patient with Fabry disease
Angiokeratoma are usually distributed on the buttocks, groin, umbilicus, upper thighs (bathing trunk distribution), and, occasionally, on the lips and oral mucosa. (Source: Burlina AP, Sims KB, Politei JM, et al. Early diagnosi...
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Linear telangiectasia on the lower lip mucosa of a patient with Fabry disease
(Source: Ezgu F, Alpsoy E, Bicik Bahcebasi Z, et al. Expert opinion on the recognition, diagnosis and management of children and adults with Fabry disease: a multidisciplinary Turkey perspective. Orphanet J Rare Dis 2022;17[1]:...
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Linear telangiectasia on the pinna of a patient with Fabry disease and sensorineural hearing loss
(Source: Ezgu F, Alpsoy E, Bicik Bahcebasi Z, et al. Expert opinion on the recognition, diagnosis and management of children and adults with Fabry disease: a multidisciplinary Turkey perspective. Orphanet J Rare Dis 2022;17[1]:...
Cardiac findings. Glycosphingolipid accumulation within myocardium, heart valves, conduction pathways, and coronary vessels occurs in hemizygous males. Hypertrophic cardiomyopathy may occur without other clinical manifestations of Fabry disease in hemizygous males (114). On the other hand, diastolic dysfunction can occur prior to the presence of left ventricular hypertrophy (177). Mitral valve insufficiency is a common occurrence, and arrhythmias and electrocardiogram changes are often noted. Small vessel myocardial ischemia and infarction are frequent late manifestations of this disorder (30). Sudden cardiac death is the more common cause of death in patients with Fabry disease (09).
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EKG findings in Fabry disease: bifascicular and first-degree atrioventricular blocks and EKG criteria of left ventricular hypertrophy
EKG findings in a 72-year-old male. (Source: Azevedo O, Cordeiro F, Gago MF, et al. Fabry disease and the heart: a comprehensive review. Int J Mol Sci 2021;22[9]:4434. Creative Commons Attribution 4.0 International [CC BY 4.0] ...
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EKG findings in Fabry disease: nonsustained ventricular tachycardia in 24-hour Holter monitoring
EKG findings in a 76-year-old male. (Source: Azevedo O, Cordeiro F, Gago MF, et al. Fabry disease and the heart: a comprehensive review. Int J Mol Sci 2021;22[9]:4434. Creative Commons Attribution 4.0 International [CC BY 4.0] ...
Pulmonary findings. Respiratory symptoms are usually not considered prominent manifestations of Fabry disease, but with age, patients complain of dyspnea, cough, and wheezing that is independent of their smoking status (21). This population also has a higher incidence of spontaneous pneumothorax and, occasionally, hemoptysis. The pulmonary symptoms are postulated to be due to fixed narrowing of airways from glycosphingolipid accumulation.
Renal findings. Progressive glycosphingolipid accumulation within the renal glomeruli and tubules and the vasculature is associated with proteinuria and gradual renal failure. Inspection of the urine with polarized light will often demonstrate casts and “Maltese crosses,” which are birefringent lipid globules. Deterioration of renal function develops, with azotemia and death occurring in the third to fifth decades, unless treatment with chronic hemodialysis or renal transplantation is provided (19; 138).
Hematoxylin-eosin staining, X400 magnified. (Source: Ezgu F, Alpsoy E, Bicik Bahcebasi Z, et al. Expert opinion on the recognition, diagnosis and management of children and adults with Fabry disease: a multidisciplinary Turkey ...
Gastrointestinal findings. Among 48 adult patients with Fabry disease and gastrointestinal manifestations, abnormal bowel habits and abdominal pain were the most common symptoms; bloating, nausea, vomiting, and reflux were also prevalent (12). Neurologic manifestations were found in 96%, along with their gastrointestinal manifestations. Dysmotility was found in fewer than 35% of wireless motility capsule tests. Colon transit time was associated with constipation severity. Gastrointestinal symptoms were associated with reduced quality of life, anxiety, and reduced work or productivity.
Ophthalmological findings. Corneal opacity that can be seen only by slit-lamp examination is usually the first ocular abnormality. These corneal changes (present in essentially all hemizygous Fabry patients) first appear as a mild generalized clouding in the subepithelial corneal layer and may progress to form whorled streaks ("cornea verticillata") (173).
Cornea verticillata (also called vortex keratopathy, whorl keratopathy, or Fleischer vortex) describes a whorl-like pattern of golden brown or gray opacities in the corneal epithelium. "Verticillata" is from the Latin noun “verticillus,” meaning "whorl.” Usually asymptomatic, it is caused by the deposition of metabolic substrates or disease byproducts in the basal epithelial layer of the cornea in Fabry disease. Cornea verticillata is not specific to Fabry disease, however, as it may also occur with other diseases (eg, multiple myeloma, neurotrophic keratitis, Lisch corneal dystrophy, epidemic keratoconjunctivitis, and iron deposition after radial keratotomy) and as a complication of some drugs (eg, amiodarone, atovaquone, chloroquine/hydroxychloroquine, gentamicin, gold salts, indomethacin, meperidine, perhexiline maleate, phenothiazines such as chlorpromazine, suramin, tamoxifen, tilorone, and the tyrosine kinase inhibitors vandetanib and osimertinib) (134). Nevertheless, cornea verticillata is most often associated with Fabry disease or amiodarone use. Chloroquine and hydroxychloroquine increase the intralysosomal pH and may cause corneal pathology by reducing the activity of the alpha-galactosidase A enzyme (76).
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Cornea verticillata (a bilateral, whorl-like corneal pattern of cream-colored lines) in a patient with Fabry disease
(Source: Burlina AP, Sims KB, Politei JM, et al. Early diagnosis of peripheral nervous system involvement in Fabry disease and treatment of neuropathic pain: the report of an expert panel. BMC Neurol 2011;11:61.)
Lenticular opacities may occur in approximately 30% of affected males and consist of granular anterior capsular and subcapsular deposits, or a characteristic posterior capsular spoke-like opacity, or “Fabry cataract” (16). The corneal and lenticular opacities, however, do not interfere with vision.
Retinal and conjunctival lesions, manifesting as tortuous and dilated vessels, may occur as part of a diffuse systemic vascular involvement. Ischemic optic neuropathy may occur secondary to cilioretinal artery occlusion or central retinal artery occlusion (54).
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Vascular tortuosity, telangiectasias, and aneurysmal changes of the conjunctival vessels in the left eye of a patient with Fabry disease
(Source: Ezgu F, Alpsoy E, Bicik Bahcebasi Z, et al. Expert opinion on the recognition, diagnosis and management of children and adults with Fabry disease: a multidisciplinary Turkey perspective. Orphanet J Rare Dis 2022;17[1]:...
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Linear telangiectasia in the conjunctiva of a patient with Fabry disease
(Source: Ezgu F, Alpsoy E, Bicik Bahcebasi Z, et al. Expert opinion on the recognition, diagnosis and management of children and adults with Fabry disease: a multidisciplinary Turkey perspective. Orphanet J Rare Dis 2022;17[1]:...
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Fundus examination of a patient with Fabry disease showing increased retinal vascular tortuosity in the right eye
(Source: Ezgu F, Alpsoy E, Bicik Bahcebasi Z, et al. Expert opinion on the recognition, diagnosis and management of children and adults with Fabry disease: a multidisciplinary Turkey perspective. Orphanet J Rare Dis 2022;17[1]:...
Corneal verticillata, hyper-reflective foci on optical coherence tomography, conjunctival vessel malformation, and retinal vessel tortuosity are prevalent, characteristic, and easily accessible in patients with Fabry disease and should be considered among the clinical diagnostic criteria for the disease (173).
Peripheral nervous system findings. Patients with Fabry disease suffer from a length-dependent small-fiber neuropathy (149; 95; 22). Dorsal root ganglia may become swollen (22).
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Photomicrographs of frozen skin sections (50 μm) from a patient with Fabry disease
Samples immunoreacted with PGP 9.5 and were processed for fluorescence microscopy with Cy3 labeled secondary antibodies. Note the lack of intraepidermal nerve fibers and persistence of fibers pertaining to the subepidermal nerv...
The most dramatic symptom in males, and often in females, affected with Fabry disease is pain in the extremities (111; 96). This is usually described as an intense burning or lancinating pain in the fingers or toes. There may also be mild persistent numbness and paresthesias in the extremities (acroparesthesia), interspersed with episodic excruciating pain. The painful crises may last for several days and may be associated with fever and an increased erythrocyte sedimentation rate. Decreased cold perception and, to a lesser extent, warm perception is a hallmark of this neuropathy (95). Exposure to cold is particularly painful (69). Autonomic nervous system dysfunction commonly manifests as chronic diarrhea, constipation, nausea, exaggerated gastrocolic reflex, reduced cutaneous flare response, and hypohidrosis (25). Priapism has been described in some patients, mostly children; it may be due to increased neuronal nitric oxide synthase (and probably endothelial nitric oxide synthase) content and the consequent elevated nitric oxide production and high arterial blood flow in the penis (100).
Cochleovestibular findings. Individuals with Fabry disease have an increased prevalence of peripheral vestibular disorders (176). Hearing impairment and vertigo are common findings, especially in males with Fabry disease (128).
Central nervous system findings. The symptoms related to the cerebrovascular complications of Fabry disease are no different than stroke symptoms from any other etiology. They include hemiparesis, vertigo, diplopia, dysarthria, nystagmus, headache, ataxia, memory loss, and hemisensory loss (115). The vertebrobasilar system was affected in 67% of hemizygotes and 60% of heterozygotes, with elongation and tortuosity of vertebral and basilar vessels noted angiographically (58). A study using MR angiography showed that the basilar artery is enlarged in male patients with Fabry disease as a whole (58). MR angiography often shows that the basilar artery is enlarged and tortuous (dolichoectasia) in male patients with Fabry disease (58; 162; 55). Indices of abnormal cerebral autoregulation on transcranial Doppler ultrasonography are significantly impaired in Fabry disease (113; 124).
In a quantitative MRI study of 50 Fabry hemizygotes, progressive cerebrovascular involvement in small- to medium-size vessels occurred over time (36). In this study, there were no patients younger than 26 years of age who had cerebrovascular disease, but all patients over 54 years of age had cerebrovascular disease, although usually these lesions were clinically silent. Strokes are common, can be the presenting symptom, and can occur in female heterozygotes as well (115; 152; 178).
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Brain MRI findings in Fabry disease: acute small-junctional infarct (DWI)
Spectrum of diffusion-weighted brain MRI findings in a 51-year-old male patient with Fabry disease. Arrow indicates acute small-junctional infarct. (Source: Ezgu F, Alpsoy E, Bicik Bahcebasi Z, et al. Expert opinion on the reco...
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Brain MRI findings in Fabry disease: chronic left mid-pons perforating infarcts (T2-weighted)
Spectrum of T2-weighted brain MRI findings in a 51-year-old male patient with Fabry disease. Chronic left mid-pons perforating infarcts (lacune type, arrow). (Source: Ezgu F, Alpsoy E, Bicik Bahcebasi Z, et al. Expert opinion o...
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Brain MRI findings in Fabry disease: accumulation of small basal perforating infarcts
Spectrum of brain MRI findings in a 51-year-old male patient with Fabry disease. Accumulation of small basal perforating infarcts: (1) right thalamic lesion; (2) emergence of left caudate lesion in 1-year interval. (Source: Ezg...
White matter lesions on MRI are common and are not typically accompanied by neurologic or cognitive abnormalities (90). Cerebral microbleeds were found by brain MRI in 30% of patients (87). In addition, these white matter lesions do not regress with enzyme replacement therapy (156). Asymptomatic white matter lesions on brain MRI were found in 16% of children with Fabry disease (97).
Spectrum of FLAIR sequence brain MRI findings in a 51-year-old male patient with Fabry disease. (Source: Ezgu F, Alpsoy E, Bicik Bahcebasi Z, et al. Expert opinion on the recognition, diagnosis and management of children and ad...
Heterozygous females. Heterozygous females may have variable manifestations of Fabry disease that can range from asymptomatic to as severe as a male with classic Fabry disease (123; 75; 07; 48; 17; 71; 70; 68; 165). Approximately 70% to 80% of affected females will have corneal opacities, but only rarely will cataracts be noted. In approximately 30% of females, a few angiokeratomas may be present in the characteristic location. Intermittent pain and paresthesia may occur and, rarely, cardiac and renal symptoms may develop. A few heterozygotes have had clinical symptoms comparable to those found in affected males, thought to be due to skewed X-inactivation (48). In a female monozygotic twin pair, wherein one girl was affected with Fabry disease and the other was asymptomatic, uneven X-inactivation and discordant gene expression were found to explain the clinical differences in these identical siblings (123).
Prognosis and complications
Fabry disease has a high cost and healthcare resource use burden and reduced quality of life compared with healthy populations (79). The following factors were identified as independent predictors of decreased health-related quality of life: classic phenotype, kidney and heart disease, stroke or transient ischemic attack, depression, and burning limb pain (172). Enzyme replacement therapy and chaperone therapy were independent determinants of improved health-related quality of life.
Most untreated hemizygous males die by 40 to 50 years of age. The median survival age of males with Fabry disease is 50 to 55 years (19; 138). Death is usually a consequence of renal failure, heart disease, or sometimes stroke (19); however, myocardial ischemia may also cause fatal complications (30). Heterozygous females have mild symptoms and a wide spectrum of disease complications. Clinical manifestations of Fabry disease can range between subtle subclinical manifestations such as corneal opacities and classic Fabry disease as described before. MRI abnormalities in the kidneys have been observed in affected males and in female carriers; however, this latter group presents a lower incidence than classically affected males (65). Cerebrovascular manifestations have been observed in carrier females (152). Therefore, Fabry disease in heterozygotes has a wide spectrum (66).
Clinical vignette
A 12-year-old boy presented to the child neurology clinic with a history of painful extremities after exercising on warm days. This began 1 to 2 years earlier and was similar to what his sister and mother had experienced at the same age. Both mother and sister, however, had milder symptoms, and at the age of 43 years, the mother was no longer troubled by this symptom. The child had also complained of diarrhea and cramping following meals. The family history was significant for a maternal uncle who died at the age of 47 and a grandfather who died at the age of 54 from complications of myocardial infarctions and multiple strokes. The clinical examination revealed a painful peripheral neuropathy affecting the distal lower extremities. Three angiokeratomas were present around the umbilicus, groin, and buttock.
Examination of the eyes demonstrated a slight clouding of the corneas, but no lenticular opacities were observed. Because of the possibility of an X-linked disease, the pathological studies obtained from the maternal uncle were reviewed. Tissue taken from the dorsal root ganglia showed an accumulation of lipids in the small sensory neurons consistent with Fabry disease in the uncle.
Leukocyte alpha-galactosidase A enzyme activity from the boy was low, thus confirming the diagnosis of Fabry disease.
Biological basis
Etiology and pathogenesis
Fabry disease is caused by a deficiency of the enzyme alpha-galactosidase A.
(Source: Deposition authors: Fujimoto Z, Kaneko S, Kobayashi H; visualization author: User:Astrojan on May 18, 2019 http://www.rcsb.org/structure/...]. Creative Commons Attributi...
Genetics. Fabry disease has often been regarded as an X-linked recessive disorder, and most published pedigrees are consistent with that form of inheritance (33).
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Family pedigree of a patient with Fabry disease showing the x-linked pattern of inheritance (1)
The index patient (propositus) is marked with a black arrow. Affected males are indicated by solid black squares; female carriers are indicated by a round black circle within the larger circle denoting a woman. Numbers within s...
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Family pedigree of a patient with Fabry disease showing the x-linked pattern of inheritance (2)
The index patient (propositus) is marked with a black arrow. Affected males are indicated by solid black squares; female carriers are indicated by a round black circle within the larger circle denoting a woman. Numbers within s...
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Family pedigree of a patient with Fabry disease showing the x-linked pattern of inheritance (3)
The index patient (propositus) is marked with a black arrow. Affected males are indicated by solid black squares; female carriers are indicated by a round black circle within the larger circle denoting a woman. Numbers within s...
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Family pedigree of a patient with Fabry disease showing the x-linked pattern of inheritance (4)
The index patient (propositus) is marked with a black arrow. Affected males are indicated by solid black squares; female carriers are indicated by a round black circle within the larger circle denoting a woman. Numbers within s...
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Family pedigree of a patient with Fabry disease showing the x-linked pattern of inheritance (5)
The index patient (propositus) is marked with a black arrow. Affected males are indicated by solid black squares; female carriers are indicated by a round black circle within the larger circle denoting a woman. Numbers within s...
However, the observation that female heterozygotes are frequently affected, albeit usually less severely than affected males, argues that Fabry disease could or should be considered X-linked dominant with reduced penetrance (96; 75; 07; 48; 06; 17; 71; 70; 68; 165; 77). As with many other X chromosome disorders, it has also been argued that Fabry disease should instead be characterized simply as inherited in an X-linked manner, without distinction as to being recessive or dominant (46).
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Clinical manifestations of Fabry disease in female heterozygotes and its multiorgan involvement
(Source: Izhar R, Borriello M, La Russa A, et al. Fabry disease in women: genetic basis, available biomarkers, and clinical manifestations. Genes [Basel] 2023;15[1]:37. Creative Commons Attribution 4.0 International [CC BY 4.0]...
Pathological findings. Multiple organs are affected in Fabry disease, but the major pathological alterations occur in the cardiovascular and renal systems secondary to glycosphingolipid accumulation.
Skin. The skin lesions consist of superficial telangiectasias and angiomas. Larger angiomas may be associated with elevation, hypertrophy, and hyperkeratosis, explaining the use of the term “angiokeratoma.” Other pathological changes may include atrophy or reduction in the number of sweat and sebaceous glands, as well as lipid accumulation in sweat glands (64).
Heart. Glycosphingolipid accumulation occurs in myocardial cells and valvular fibrocytes (41), causing the hypertrophy of the chamber walls, along with valvular involvement. Coronary vessels are also affected by lipid storage within their endothelial cells.
Lungs. Pathological studies have demonstrated laminated inclusions in ciliated epithelial cells, goblet cells, capillary endothelium, type II pneumocytes, and in pulmonary and bronchial smooth muscles (21).
Kidney. The first lipid deposition in Fabry kidney begins in endothelial and epithelial cells of the glomerulus and later affects proximal tubules and interstitial cells (108). Eventually, renal vessels also show glycosphingolipid accumulation.
Eye. The eye demonstrates glycosphingolipid deposits within the ocular vessels, iris, and connective tissue of the lens and cornea (59). A corneal dystrophy is seen, thought to be secondary to subepithelial ridges or reduplication of the basement membrane (59).
Nervous system. The CNS is affected by a cerebral vasculopathy (138) and accumulates lipids in several groups of neurons, many belonging to the autonomic nervous system. These areas involved include the supraoptic, preoptic, and paraventricular nuclei, nucleus basalis of amygdala, anterior thalamus, subiculum of hippocampus, Edinger-Westphal nucleus, mesencephalic nucleus of the fifth cranial nerve, substantia nigra, salivary nuclei, dorsal nucleus of the vagus, nucleus gracilis and cuneatus, reticular substance of pons and medulla, and intermediolateral cell columns of the thoracic cord (120; 82; 43). Peripheral nervous system structures that show lipid accumulation include the small ganglion cells in dorsal horn and loss of small myelinated and unmyelinated nerves (111; 24).
See Table 1 below for chemical storage.
Table 1. Glycosphingolipids that Accumulate in Fabry Disease
Globotriaosyl-ceramide |
{Gal(alpha1---> 4)Gal(beta1---> 4) |
Galabiosyl-ceramide |
{Gal(alpha1---> 4)Glc(beta1--> 1')Cer} |
Blood Group B glycolipid |
{Gal(alpha1---> 3)Gal(2< ---1alphaFuc) |
Blood Group B1 glycolipid |
{Gal(alpha1---> 3)Gal(2< ---1alphaFuc) |
Globotriaosylceramide accumulates in many tissues, including kidney, aorta, spleen, liver, autonomic ganglia, lymph nodes, striated muscle, and prostate (43). Within the central and peripheral nervous systems, histologic lipid staining is caused by storage of globotriaosylceramide (82). Using immunocytochemical techniques with a monoclonal antibody to globotriaosylceramide, more widespread neuronal storage of this lipid could be demonstrated in layers 5 and 6 of the neocortex, pigmented neurons in the substantia nigra, substantia gelatinosa, and motor neurons (45). Despite this neuronal “accumulation,” Fabry disease is not a primary neuronal disorder. Typically, the only evident CNS neuronal dysfunction or loss occurs secondarily in association with ischemic lesions (103). Galabiosylceramide (digalactosylceramide) appears to be more tissue-specific because it is stored primarily in kidney, pancreas, right heart structures, lung, and urinary sediment (43). Patients with blood groups B or AB, who possess the blood group B antigen, were previously thought to have a more severe form of Fabry disease, but more recent studies dispelled this notion (92).
Biochemistry of alpha-galactosidase A. The biochemical defect in Fabry disease is the deficiency of the alpha-galactosidase A enzyme.
Mutations in the GLA gene alter the structure of alpha-galactosidase A and lead to its markedly deficient or absent activity (34).
(Left side) Functional alpha-gal-A activity in a person with no mutation in GLA gene or absent activity. As a result, there is no accumulation of unwanted substrate in the lysosome. Also, the enzyme is responsible for removing ...
The glycosphingolipids (such as globotriaosylceramide, digalactosylceramide, and galabiosylceramide) have in common a terminal alpha-galactosyl moiety that is cleaved by the alpha-galactosidase A enzyme.
Thus, a deficiency or defect in the enzyme results in the accumulation of various glycosphingolipids with terminal alpha-D-galactosyl residues, including globotriaosylceramide and digalactosylceramide.