Fabry disease: Clinical features and diagnosis

INTRODUCTION — Fabry disease, also called Anderson-Fabry disease, is the second most prevalent lysosomal disease after Gaucher disease. It is an X-linked inborn error of the glycosphingolipid metabolic pathway that results in accumulation of glycosphingolipids, especially globotriaosylceramide (Gb3) in a wide variety of cells, thereby leading to the protean manifestations of the disease [1]. The hydrophilic deacylated derivative globotriaosylsphingosine (lysoGb3) is thought to have cytotoxic, proinflammatory, and profibrotic effects [2].

This topic provides an overview of the clinical manifestations and diagnosis of Fabry disease. The cardiac, neurologic, and kidney manifestations, and the treatment of Fabry disease, are discussed elsewhere:

●(See "Fabry disease: Cardiovascular disease".)

●(See "Fabry disease: Neurologic manifestations".)

●(See "Fabry disease: Kidney manifestations".)

●(See "Fabry disease: Treatment and prognosis".)

EPIDEMIOLOGY — The prevalence of classic Fabry disease is estimated to range from 1:8454 to 1:117,000 males [3-5], and the disease is seen across all ethnic and racial groups [5].

The prevalence of Fabry disease is probably underestimated given incomplete ascertainment. This is likely since [5,6]:

●The manifestations of the disease are nonspecific.

●The diagnosis is often not considered by clinicians, given the rarity of the disease.

●The wrong diagnosis is often made initially. As an example, in the 366 European patients with Fabry disease participating in the Fabry Outcome Survey, the mean delay to correct diagnosis after symptom onset was estimated to be 13.7 and 16.3 years for males and females, respectively [6]. While this delay in diagnosis has not diminished in more recent years, the delay in treatment initiation has significantly decreased [7].

●Late-onset mutations, cardiac, and renal variants may have delayed onset or varying presentations, further delaying diagnosis [8].

●Phenotypic variation in females may also complicate diagnosis [9,10].

Large genetic screening programs, which do not rely upon the development of clinical symptoms, suggest that Fabry disease is more common than previously suspected. Mutations associated with classic manifestations of Fabry disease are present in approximately 1:22,000 to 1:40,000 males [8,11], and mutations associated with atypical, so called "later-onset", presentations are present in approximately 1:1000 to 1:3000 males and 1:6000 to 1:40,000 females [8,11-15]. In the United States and Europe, by far the most common mutation is the A143T variant with an incidence of 1 in 8454 in newborns in the state of Illinois [16]. There is an extraordinary occurrence of an intervening sequence mutation (IVS4+919G>A) associated with a cardiac variant founder effect in Taiwan, which is present in 1:1600 male newborns [13] and in twice as many female newborns [17]. (See 'Genetics' below.)

PATHOPHYSIOLOGY — The metabolic defect in Fabry disease is deficiency of the lysosomal hydrolase alpha-galactosidase A (alpha-Gal A), which primarily catalyzes the hydrolytic cleavage of the terminal galactose from alpha D-galactosyl moieties of glycolipids such as globotriaosylceramide (Gb3) and glycoproteins [18,19]. The threshold level of alpha-Gal A activity below which clinically significant Fabry disease occurs is thought to be 30 to 35 percent of the mean normal control [20]. Males with the classic form of Fabry disease are "null mutants" with alpha-Gal A activity that is almost always less than 1 percent of the normal mean. Higher alpha-Gal A activity is most often present in females and those with atypical variants, in whom activity may be in the lower levels of the normal range. There is a relationship, albeit imprecise, between enzyme activity and disease symptoms; enzyme activity is the primary predictor of the likelihood to develop Fabry-related complications [3,21]. (See 'Classic Fabry disease' below and 'Heterozygous females' below and 'Atypical (later-onset) variants' below.)

Gb3 is an intermediate in the degradative pathway of globoside. Globoside, a major glycosphingolipid in the red cell membrane and the kidney, is composed of ceramide attached to three sugar residues and an N-acetylgalactosamine residue (ceramide-Glc-Gal-Gal-GalNAc). Gb3 is metabolized in lysosomes, particularly in the spleen, liver, and bone marrow. In the absence of significant alpha-Gal A activity, Gb3 accumulates in various cells and tissues. Tissue accumulation of Gb3 is inversely correlated with residual alpha-Gal A activity in leukocytes and many other cell types [3]. The hydrophilic deacylated derivatives of Gb3 (globotriaosylsphingosine [lysoGb3] and its analogues) are thought to have cytotoxic, proinflammatory, and profibrotic effects [2,22].

The accumulation of Gb3 is particularly prominent in the vascular endothelium (at levels up to 460-fold higher than normal), vascular smooth muscle cells, and pericytes [3,19,23]. The deposition of glycosphingolipid in these cells may lead to death of smooth muscle cells, vascular occlusion, ischemia, and infarction.

Accumulation of Gb3 in autonomic ganglia; dorsal root ganglia; kidney glomerular (primarily podocytes [24]), tubular, and interstitial cells; cardiac muscle cells, conduction fibers, and valvular fibrocytes; vascular smooth muscle cells; and vascular and lymphatic endothelial cells in the cornea may lead to the myriad other manifestations of the disease. The actual clinical involvement varies significantly among different organs, which likely represents various rates of sphingolipid metabolism in different tissues [25].

Gb3 deposition may be only partially responsible for the manifestations of the disease, and other as-yet unexplained factors might also contribute. In one report of 57 symptomatic female patients with confirmed Fabry genotype who underwent a skin biopsy, only one patient had visible glycolipid accumulation in endothelial cells by light microscopy, while 10 to 50 percent had mild accumulation in other cell types [26]. Cardiac, kidney, or cerebrovascular abnormalities were documented in 90 percent of these females, but these important target organs were not biopsied in this study.

GENETICS — Fabry disease is caused by pathogenic variants in the alpha-galactosidase A (alpha-Gal A; galactosidase alpha [GLA]) gene mapped to the long arm (Xq22.1 region) of the X chromosome [27] and is inherited as an X-linked disorder. This mode of inheritance leads to important clinical characteristics in affected families:

●Males with Fabry disease are hemizygous and pass the Fabry genetic variant on to all their daughters, who are heterozygotes, but to none of their sons. In general, males are more severely affected than females. (See 'Classic Fabry disease' below.)

●Females with Fabry disease are heterozygous for the Fabry gene mutation and have a 50 percent chance of passing the gene on to daughters or sons. Female heterozygotes have a variable disease course that ranges from asymptomatic disease to a severe phenotype resembling that seen in males. This phenotypic variation may be due in large part to random X-chromosome inactivation, by which some cells will have the X chromosome with the defective gene activated and others will have the X chromosome with the functioning gene activated. The phenotypic extremes in heterozygous females, at least in part, represent an example of skewed (nonrandom) X-chromosome inactivation [9]. However, Fabry phenotype cardiomyocytes [28] and podocytes [29] may adversely affect their non-Fabry phenotype neighboring cardiomyocytes and podocytes in females. Thus, the severity of symptoms and organ involvement depends upon which organs or tissues have the mutated gene activated in a significant majority of the cells [9,10,30]. (See 'Heterozygous females' below.)

Over a thousand mutations in the GLA gene have been identified [31]. Most kindreds have specific, or private, mutations, and de novo mutations are rare [32]. The severity of symptoms may vary among individuals depending upon the specific GLA mutation within their family and their age and sex. Efforts to establish genotype-phenotype correlations have been limited by the fact that most families have a private mutation, and phenotypic variation exists even among patients with the same mutation. In general, mutations that result in little to no alpha-Gal A activity cause the classic Fabry phenotype, and those that result in residual alpha-Gal A activity cause the atypical, "later-onset" phenotype [33]. In addition, the interaction between alpha-Gal A deficiency and other genetic, epigenetic, and environmental factors may also influence disease severity in the individual patient [20].

CLINICAL PRESENTATION — Patients with Fabry disease may present with a spectrum of clinical manifestations, ranging from the severe classic phenotype in males to asymptomatic disease in some females, with a variety of clinical presentations in between. The age of symptom onset is more consistent in male hemizygotes with a classic presentation than in female heterozygotes; approximately 80 percent of males have neurologic, dermatologic, and kidney and cardiac manifestations by the second, third, and fifth decades of life, respectively [6]. Males with atypical variants may present even later in life and, in the absence of an established family history of Fabry disease, are usually diagnosed during evaluations for cardiomegaly, proteinuria, or stroke [21,32,34].

Classic Fabry disease — The classic form of Fabry disease is the most severe clinical phenotype and occurs predominantly in males, although some heterozygous females have a more severe phenotype that resembles classic Fabry disease in males. Males with classic Fabry disease have little or no functional alpha-galactosidase A (alpha-Gal A) enzyme activity (<1 percent of the normal mean). Although variability exists, the symptoms of Fabry disease tend to appear in a predictable order in classically affected males (table 1) [23,32,35]. Clinical manifestations begin in childhood or adolescence and include [3,6,23]:

●Severe neuropathic or limb pain (acroparesthesias), which may be precipitated by stress, extremes of heat or cold, and physical exertion. Neuropathic symptoms occur in more than 75 percent of patients with a mean age of onset of 10 years. (See "Fabry disease: Neurologic manifestations", section on 'Small-fiber peripheral neuropathy'.)

●Telangiectasias and angiokeratomas, the latter commonly in groin, hip, and periumbilical areas, are characteristic (picture 1 and picture 2). Dermatologic manifestations of Fabry disease occur in more than 70 percent of male patients with a mean age of onset of 17 years but may be absent or minimal in females.

●Gastrointestinal symptoms, such as abdominal pain, recurrent nausea and vomiting, and either diarrhea or constipation occur in approximately 20 to 70 percent of patients [36,37]. These symptoms appear to be caused by the deposition of globotriaosylceramide (Gb3) in autonomic ganglia of the bowel and mesenteric blood vessels, leading to intestinal dysmotility, impaired autonomic function, vasculopathy, myopathy, and bleeding [38].

●Corneal opacities (cornea verticillata) are a characteristic feature seen relatively early on in almost all hemizygous males and most heterozygous females [39,40]. A formal slit-lamp examination is usually necessary to appreciate these corneal opacities. In addition, anterior and posterior subcapsular cataracts (the "Fabry cataract") can be seen in approximately 30 percent of affected males. Other ocular findings include aneurysmal dilatation and tortuosity of conjunctival and retinal vessels and subconjunctival lymphangiectasia [41]. Other than subcapsular cataracts, the ocular manifestations of Fabry disease do not cause visual impairment. Dry eye symptoms are associated with the subconjunctival lymphangiectasia.

●Kidney manifestations such as proteinuria, isosthenuria, polyuria, and polydipsia or otherwise unexplained kidney function impairment are common. Kidney disease, initially manifesting as proteinuria, occurs in more than 80 percent of untreated male patients with a mean age of 35 to 40 years. A more detailed discussion of the kidney manifestations in Fabry disease is presented separately. (See "Fabry disease: Kidney manifestations".)

●Other nonspecific manifestations, which tend to worsen in early adulthood, include heat, cold, and exercise intolerance; hypohidrosis (or, infrequently, hyperhidrosis); dry mouth; and decreased tears [42-44]. These manifestations occur in approximately 50 to 70 percent of patients, often by the fourth decade. Hearing loss is common, may be gradual or sudden in onset, may be unilateral or bilateral, and is typically more frequent and severe in males than in females [45]. Tinnitus and vertigo are also common [46]. Tremor and other movement-type disorders can also be seen in Fabry disease [47].

In adulthood, there may be progressive cardiac and cerebrovascular involvement, and cardiac complications account for the majority of deaths associated with Fabry disease [48]:

●Cardiac involvement includes concentric left ventricular hypertrophy (LVH), myocardial fibrosis, heart failure, coronary artery and arteriolar disease, aortic and mitral valve abnormalities, aortic root dilation, and conduction abnormalities. Cardiac manifestations occur in more than 80 percent of male patients with classic Fabry disease, with a mean age of symptom onset of 42 years. In some patients, these manifestations, particularly LVH, are the only recognized manifestations of the disease. In young females, myocardial fibrosis may develop without apparent LVH [49]. Fabry disease is a potential cause of unexplained LVH or hypertrophic cardiomyopathy and is included in the genetic screening panels for hypertrophic cardiomyopathy [50]. Arrhythmias are also common and potentially fatal manifestations of Fabry cardiac involvement [51]. (See "Fabry disease: Cardiovascular disease", section on 'Clinical features' and "Hypertrophic cardiomyopathy: Gene mutations and clinical genetic testing", section on 'Alpha-galactosidase A and Fabry disease'.)

●Cerebrovascular involvement may lead to transient ischemic attacks and ischemic strokes, and it can cause a wide range of neurologic symptoms, including blindness and sudden deafness. In addition, enlargement of large cranial arteries (dolichoectasia) may occur [52]. Transient ischemic attacks and strokes occur in approximately 25 percent of patients with a mean age of onset of 40 years [53]. In addition, non-stroke central nervous system involvement in Fabry disease including Parkinson disease symptoms, depression, and cognitive issues have been described [54]. (See "Fabry disease: Neurologic manifestations".)

In addition to the major symptoms and signs mentioned above, patients with classic Fabry disease may have other clinical manifestations, including pulmonary involvement such as chronic bronchitis, wheezing, or dyspnea [55]; lymphatic involvement, such as lymphedema [56,57]; subconjunctival lymphangiectasia [41]; priapism [58,59]; hearing loss [60,61]; nonimmune hypothyroidism [62]; azoospermia [63]; and osteopenia or osteoporosis [64] and aseptic osteonecrosis [65]. Psychological manifestations, such as depression, anxiety, and chronic fatigue, are also common [66] and can lead to suicide [67]. Dysmorphic facial features including periorbital fullness, prominent lobules of the ears, thickening of the lips, and bulbous nose have been described [68]. Such facial characteristics are not found in females or males with significant residual alpha-Gal A activity.

Heterozygous females — Historically, females were considered to be asymptomatic carriers of defective GLA genes who were not vulnerable to the symptoms and vital organ abnormalities of Fabry disease. However, studies have shown that clinical manifestations in heterozygous females can vary widely from no apparent clinical disease to full classic expression of the disease [26,37,69-72]. This phenotypic variation may be due, at least in part, to skewed (nonrandom) X-chromosome inactivation [9], which results in a higher percentage of X chromosome with the disease mutation being expressed in affected organs. The onset of clinical manifestations in females roughly parallels that in males, but the prevalence of signs and symptoms at any given age is lower in females [71]. (See 'Genetics' above.)

Heterozygous females may exhibit any or all of the symptoms and signs of Fabry disease, including acroparesthesias (23 to 90 percent), angiokeratomas (10 to 63 percent) [26,69], hypohidrosis (1 to 28 percent) [69,70], cornea verticillata (70 to 90 percent) [70], and chronic abdominal pain (21 to 33 percent) and diarrhea (17 to 19 percent) [26,36,71].

With increasing age, females may develop cardiac involvement (such as fibrosis, LVH, arrhythmias, and valvular disease) and cerebrovascular disease (transient ischemic attacks and strokes). Kidney manifestations, such as proteinuria, isosthenuria, and chronic kidney disease (CKD), occur less frequently than in males [21,37,71]. However, when females do develop CKD, the mean time for progression to end-stage kidney disease (ESKD) is similar to that in males [73]. Cardiac, cerebrovascular, and kidney disease typically present one decade or more later than in males. In a study of 1077 females enrolled in the Fabry Registry, approximately 70 percent reported symptoms or signs of Fabry disease; the median age of symptom onset was 13 years [71]. Twenty percent of patients developed major cardiac, cerebrovascular, or kidney events at a median age of 46 years.

Atypical (later-onset) variants — Patients with atypical, "later-onset" variants of Fabry disease usually present later in life (third to seventh decades of life) than those with the classic form of the disease [21]. They have residual alpha-Gal A activity (between 2 and 30 percent of the normal mean) and may not have Gb3 inclusions in capillary endothelial cells or angiokeratomas. Many do not display the classical features of Fabry disease until the seventh to eighth decade of life [34] (see 'Classic Fabry disease' above), and their disease may sometimes be dominated by a particular organ system, most commonly the heart. In the absence of a family history, the diagnosis is often made incidentally during an evaluation of unexplained LVH, heart failure, arrhythmias, proteinuria, kidney failure, or cryptogenic stroke.

Cardiac variant — The cardiac variant of Fabry disease is a common later-onset variant, the heart being the organ most susceptible to an abnormally low alpha-Gal A activity. Patients with the cardiac variant of Fabry disease are generally asymptomatic for much of their lives and present in the fifth to eighth decade of life with LVH, hypertrophic cardiomyopathy, conduction abnormalities, and arrhythmias [74-76]. Although the cardiac variant was once thought to be rare, studies have shown that this diagnosis may be responsible for up to 4 percent of cases of unexplained hypertrophic cardiomyopathy [50,75-79]. It is the most common form of Fabry disease in Taiwan, where 82 percent have the IVS4+919G>A mutation [13]. Cardiac disease is also a prominent feature in the most common later-onset variant in Western countries, N215S [80]. A more detailed discussion of the cardiac manifestations of Fabry disease is presented elsewhere. (See "Fabry disease: Cardiovascular disease".)

In addition, patients with the cardiac variant may have mild to moderate proteinuria in the setting of normal or mildly impaired kidney function. Kidney histology in such patients reveals lysosomal glycosphingolipid deposition almost exclusively within podocytes [81] but not always in all of these cells. These patients may also develop kidney failure [34].

Renal variant — Some patients with Fabry disease may present with disease limited to the kidney. (See "Fabry disease: Kidney manifestations".)

The renal variant of Fabry disease was originally described in a study of 514 Japanese patients on chronic dialysis, six (1.2 percent) of whom were found to have low plasma and leukocyte alpha-Gal A activity and a mutation in the alpha-Gal A gene [82]. All patients had been previously misdiagnosed with chronic glomerulonephritis and had initiated hemodialysis at 25 to 56 years of age. Five of the six patients did not have angiokeratomas, acroparesthesias, hypohidrosis, or corneal opacities, while one patient, who also had a family history of kidney disease, reported acroparesthesias and hypohidrosis. Reexamination of the kidney biopsy of this patient revealed glycosphingolipid deposits in podocytes and glomerular capillary endothelial cells. Pedigree extension studies in a Chinese family with the E66Q mutation are consistent with identification of this mutation as a renal variant even though some of those affected also had LVH [83].

The findings of this study and others [84-86] suggest that the renal variant of Fabry disease may be underdiagnosed among patients with ESKD. It remains unclear if patients on dialysis or undergoing kidney transplantation should be screened for Fabry disease, although testing those who do not have a clear etiology for their kidney failure is a reasonable approach. The consequences of using an affected family member as an organ donor [87] as well as the potential benefit to other undiagnosed family members provide strong support for considering screening for Fabry disease in the ESKD population [87,88], especially if the ESKD diagnosis is uncertain. It is possible that some patients with the renal variant of Fabry disease may subsequently develop other Fabry disease complications (such as cardiac involvement) at a later age. Thus, clinicians should provide complete organ system follow-up, as for any patient with Fabry disease.

DIAGNOSIS — Fabry disease should be suspected in patients with a family history of Fabry disease or those who present with the clinical manifestations or laboratory abnormalities discussed above. The diagnosis is typically confirmed by biochemical and/or molecular genetic testing (algorithm 1), with the latter approach being the final determinant.

When to suspect Fabry disease — An evaluation for Fabry disease should be performed in males or females with at least one of the following clinical features suggestive of the diagnosis, particularly:

●Intermittent episodes of burning pain in the extremities (acroparesthesias)

●Cutaneous vascular lesions (angiokeratomas)

●Diminished perspiration (hypo- or anhidrosis)

●Characteristic corneal and lenticular opacities

●Abdominal pain, nausea, and/or diarrhea of unknown etiology in young adulthood or any symptoms consistent with irritable bowel syndrome

●Left ventricular hypertrophy (LVH) of unknown etiology, particularly in young adults

●Arrhythmias of unknown etiology, particularly in young adults

●Stroke of unknown etiology at any age

●Chronic kidney disease (CKD) and/or proteinuria of unknown etiology

●Multiple renal sinus and/or renal pelvis cysts discovered incidentally

●Recurrent fever of unknown origin

A family history suggestive of the disorder (ie, history of unexplained gastrointestinal symptoms, extremity pain, and/or kidney disease, ischemic stroke, or cardiac disease in one or more family members) is particularly helpful and presents the opportunity for screening the entire pedigree.

Specific issues related to case findings in family members of patients with Fabry disease are presented below (see 'Screening family members' below).

Initial assessment — An initial evaluation should consist of the following [32,35,89]:

●Detailed past medical history and review of systems. Clinical symptoms or signs such as neuropathic pain; heat intolerance (usually associated with exercise intolerance and avoidance of outdoors in summer months); decreased production of sweat, tears, or saliva; diarrhea; abdominal pain; angiokeratomas; and foamy urine should be carefully documented at baseline. Any history of transient ischemic attacks or ischemic strokes (particularly involving the posterior circulation) and myocardial disease should be thoroughly explored. (See 'Clinical presentation' above.)

●Detailed family history that focuses on relatives with unexplained neurologic, kidney, or heart disease or premature death, particularly when any of these conditions appear to be transmitted as an X-linked trait (see 'Genetics' above). In the National Institutes of Health (NIH) series, family history contributed to the diagnosis in 46 percent of patients [90].

●Careful physical examination, looking for angiokeratomas, telangiectasias, hypo- or anhydrosis, corneal opacities, lymphedema, abnormal cardiac examination (evidence of LVH, arrhythmia).

●Routine laboratory tests to evaluate kidney function such as creatinine, urinalysis with examination of the urine sediment, and spot urine protein-to-creatinine (or urine albumin-to-creatinine) ratio. With kidney involvement, urine microscopy may reveal oval fat bodies (degenerating tubular epithelial cells with lipid inclusions) with a lamellar structure and a Maltese cross pattern under polarized microscopy (picture 3); this is similar to what may be seen with nephrotic-range proteinuria of any cause. (See "Urinalysis in the diagnosis of kidney disease" and "Urinalysis in the diagnosis of kidney disease", section on 'Urinary lipids'.)

●Electrocardiogram to evaluate for LVH and conduction defects. In females, LVH may be absent and cardiac magnetic resonance imaging (MRI) may be required to identify fibrotic lesions of Fabry disease, which, in females, can precede measurable LVH [49]. (See "Fabry disease: Cardiovascular disease", section on 'Electrocardiogram'.)

●In addition, some clinicians obtain a baseline MRI of the brain as part of the initial evaluation, particularly in patients who present with neurologic manifestations. Findings on MRI may be normal or show evidence of an old ischemic lesion, white matter abnormalities on T2-weighted or fluid-attenuated inversion recovery (FLAIR) images, pulvinar lesions on T1-weighted images, or increased arterial diameters in the posterior cerebral circulation [91,92]. (See 'Classic Fabry disease' above and "Fabry disease: Neurologic manifestations".)

Establishing the diagnosis

Diagnosis in males — In all male patients suspected of having Fabry disease, we measure leukocyte alpha-galactosidase A (alpha-Gal A) activity as the initial diagnostic assay [32,93,94] (see 'Tests used in the diagnosis of Fabry disease' below). Our subsequent approach is as follows (algorithm 1):

●In males with virtually undetectable (<3 percent) alpha-Gal A leukocyte activity, a diagnosis of classic Fabry disease can be established. Genetic testing should then be performed. Genetic testing in this setting facilitates diagnosis and genetic counseling in the patient's family (particularly in females) and further genetic assessment (www.galafoldamenabilitytable.com/hcp) or in vivo testing may be needed to establish the patient's amenability to treatment with chaperone therapy (ie, migalastat) [95]. (See 'Genetic testing' below and "Fabry disease: Treatment and prognosis", section on 'Chaperone therapy (migalastat)'.)

●In males with decreased but detectable (3 to 35 percent) alpha-Gal A leukocyte activity, a diagnosis of Fabry disease is worth strong consideration since, as mentioned above, some hemizygous males and males with later-onset/atypical variants may have alpha-Gal A leukocyte activity within this range. In such patients, genetic testing to search for a disease-causing mutation in the GLA gene should be performed to confirm the diagnosis for genetic counseling, followed by testing to establish the patient's amenability to treatment with chaperone therapy. If no disease-causing mutation is identified on routine genetic testing and the suspicion remains high, gene-targeted deletion/duplication assays should be performed [96,97]. If these tests are negative, a diagnosis of Fabry disease can be ruled out. If the patient is found to have a genetic variant of unknown significance, and alpha-Gal A leukocyte activity is not clearly below 30 percent of the mean normal, biopsy of an affected tissue or organ (eg, the kidney, heart, skin) with demonstration of elevated globotriaosylceramide (Gb3) by mass spectroscopy may be helpful in confirming the diagnosis [98,99].

●In males with alpha-Gal A leukocyte activity >35 percent of mean normal, a diagnosis of Fabry disease cannot be established.

Alternatively, some male patients may be diagnosed by sending symptom-specific gene panels that include the GLA gene as one of many genes tested. Other patients may learn about their diagnosis from commercial genetic testing services that they access to learn about ancestry. Such patients diagnosed by commercial genetic testing should also have their alpha-Gal A activity level measured. (See 'Alternative diagnostic approach' below.)

Diagnosis in females — In all female patients suspected of having Fabry disease, we perform genetic mutational analysis of the GLA gene as the initial diagnostic assay (algorithm 1) [32,93,94]. Measurement of alpha-Gal A activity in heterozygous females is unreliable because heterozygotes have variable levels of alpha-Gal A activity that can overlap with levels found in healthy controls. Thus, genetic testing is required to make the diagnosis of Fabry disease among females.

If no disease-causing mutation is identified, a diagnosis of Fabry disease can be ruled out. Due to the effect of lyonization (early embryonic random deletion of the X chromosome), even females with disease-causing mutations may have significant phenotypic variation. Biopsy of routinely affected organs (eg, the kidney) with demonstration of elevated Gb3 by electron microscopy [100] or mass spectroscopy may be helpful in confirming the diagnosis and provide an estimation of histologic involvement [98,99].

Alternative diagnostic approach — Given the sometimes nonspecific nature of Fabry disease signs and symptoms, an alternative diagnostic approach is to screen for the disease using symptom-specific gene panels (similar to genetic screening panels used for hypertrophic cardiomyopathy) that include the GLA gene as one of many genes tested. Such gene panels can test for multiple possible causative genetic abnormalities, including Fabry disease. If screening with a gene panel reveals a mutation consistent with Fabry disease, testing to determine the implications of the mutation for each individual should be completed. This includes testing of alpha-Gal A activity, globotriaosylsphingosine (lysoGb3) levels (if indicated, as in females with alpha-Gal A activity within the normal range), and if the diagnosis is confirmed, a full organ assessment as detailed above (see 'Initial assessment' above). If the evaluation is equivocal, biopsy of an affected organ may be indicated to establish the diagnosis.

Tests used in the diagnosis of Fabry disease — The diagnosis of Fabry disease is typically established with a combination of biochemical and molecular genetic testing and/or by family history, although incidental findings on kidney or cardiac biopsies may also lead to the diagnosis.

Enzymatic assay for alpha-Gal A activity — After a thorough clinical evaluation, measurement of alpha-galactosidase A (alpha-Gal A) activity is the first step in the laboratory diagnosis of male patients suspected of having Fabry disease. Alpha-Gal A activity can be measured in leukocytes, plasma, fibroblasts, or dried blood spots (DBS), although measurement of leukocyte alpha-Gal A activity is the standard enzymatic test at most laboratories. The sensitivity and specificity of the alpha-Gal A assay using leukocytes approaches 100 percent in classically affected males, but the assay will identify less than 50 percent of female carriers. Analysis of plasma alpha-galactosidase may be less sensitive than assay of enzyme activity in leukocytes [101]. Based upon the available knowledge, neither end-stage kidney disease (ESKD) nor dialysis affects the enzyme assay.

Although different methods have been used to describe the results, enzymatic activity level is most often expressed as the percent of mean normal [3]. The enzymatic level can vary by population tested:

●Alpha-Gal A activity in leukocytes is undetectable in over 50 percent of hemizygous classic males and is usually less than 4 percent of mean normal control levels in the remainder [3].

●Levels in female carriers range from normal to very low [90].

●Cardiac variants, an atypical form of this disease, have 1 to 30 percent of normal activity levels.

Genetic testing — Mutational analysis of the gene encoding alpha-Gal A, or galactosidase alpha (GLA), is the gold-standard assay to confirm the diagnosis of Fabry disease in males or females. Routine analysis, which consists of sequencing the coding region and exon-intron boundaries of the GLA gene, can detect a sequence variant in more than 97 percent of males and females with abnormal alpha-Gal A activity. A small number of mutations are not detected by routine analysis and require additional procedures such as gene-targeted deletion/duplication analysis for identification. (See 'Genetics' above.)

Genotyping is recommended for all Fabry families since this knowledge may be particularly relevant for identifying other affected members of the family and for future therapies utilizing synthetic chaperones [102]. Since more than 1000 distinct mutations have thus far been identified, identification of a mutation in a new family requires essentially complete resequencing of the gene. Genetic analysis is only done at selected laboratories [89].

Gb3 and lysoGb3 levels — Globotriaosylceramide (Gb3) and globotriaosylsphingosine (lysoGb3), a degradation product of Gb3, can be detected in the plasma and urine of patients with Fabry disease and have been proposed as potential biomarkers for diagnosis and monitoring disease activity [103-107]. Some, but not all, experts routinely measure Gb3 and lysoGb3 levels (eg, yearly in patients with confirmed Fabry disease). However, lysoGb3 may not decline in female patients who start with close to normal lysoGb3 levels, making it an unreliable pharmacologic marker in some females [108,109].

The role of these markers in the diagnosis of patients with Fabry disease remains limited for the following reasons:

●Plasma levels of Gb3 are elevated in hemizygous males but are normal or only slightly elevated in heterozygous females.

●Some, but not all, studies have shown a relationship between urine Gb3 levels and Fabry disease severity and response to treatment [110-113].

●Plasma levels of lysoGb3 are elevated in hemizygous males and, to a lesser extent, in heterozygous females with classic Fabry disease symptoms [104,106,107]. However, plasma lysoGb3 levels may not always correlate with disease manifestations in males and correlate only weakly with manifestations in females [104].

●Plasma lysoGb3 is elevated to a similar range in other lysosomal diseases such as Gaucher and Krabbe disease [114].

However, plasma and urine lysoGb3 levels, if elevated, may help to confirm the diagnosis of Fabry disease among patients who are found to have a GLA gene variant of uncertain significance. In one study of 124 patients with alpha-Gal A mutations, those with a novel GLA variant and organ involvement consistent with Fabry disease also had plasma lysoGb3 levels ≥2.7 ng/mL [115]. By contrast, those with a novel variant and no organ involvement had plasma lysoGb3 levels <2.7 ng/mL.

Plasma and urine lysoGb3 and Gb3 levels may be useful as pharmacodynamic markers for monitoring the effects of enzyme replacement therapy (ERT) or pharmacologic chaperone therapy (eg, migalastat). As an example, in patients receiving ERT, these biomarkers may progressively increase when such patients develop neutralizing antibodies to the recombinant enzyme [116,117]. However, lysoGb3 may not decline in treated patients with Fabry disease who initiate therapy with near-normal levels of lysoGb3, despite clinical improvement [109]. In patients receiving a pharmacologic chaperone, monitoring plasma and urine lysoGb3 and Gb3 levels may be important to make sure that the chaperone does not excessively inhibit alpha-Gal A activity. LysoGb3 levels may also be a useful indicator of treatment adherence in patients on chaperone therapy. (See "Fabry disease: Treatment and prognosis", section on 'Chaperone therapy (migalastat)'.)

Tissue biopsy — In some cases, biopsy of skin or, more rarely, culture of skin fibroblasts may be helpful in establishing the diagnosis but is usually done only if no other means of diagnosis are available. Skin biopsy can demonstrate the characteristic glycolipid deposits in a relatively noninvasive way but is not a reliable approach for confirming the diagnosis of significant organ involvement in Fabry disease [23] and may not be helpful in females [118].

Kidney biopsy may be helpful in establishing the diagnosis. The diagnosis of Fabry disease is sometimes made serendipitously when a kidney biopsy is obtained to diagnose the cause of proteinuria and/or decreased kidney function [119,120]. A kidney biopsy may be of particular use when patients have nephrotic syndrome, gross hematuria, or other symptoms that require exclusion of other diagnoses. (See "Fabry disease: Kidney manifestations", section on 'Pathology'.)

A kidney biopsy can also be useful in determining the extent of tissue involvement in females, patients with atypical variants, and patients with variants of unknown significance [121], even in the setting of normal kidney function. Kidney biopsies may be used to inform prognosis [122] and as measures of treatment outcomes [123-125].

Endomyocardial biopsies are routinely performed in some centers where cardiac variants are the dominant form of Fabry disease [126].

As previously mentioned, the kidney or cardiac biopsy may be essential in confirming the diagnosis of Fabry disease in patients who have newly described GLA variants with unknown significance [98,99]. However, drug-induced kidney pathological findings suggestive of Fabry disease can be observed in patients who do not have Fabry disease [127,128].

Follow-up assessment — Once diagnosed, patients with Fabry disease, or asymptomatic heterozygote females, should be followed closely using an interdisciplinary approach that involves regular evaluation by genetics, nephrology, cardiology, and neurology, with input from dermatology, ophthalmology, and psychiatry as required [32,129]:

●Patients should undergo annual reevaluation with documentation of any clinical symptoms or signs. The annual examinations should also include routine hematology and chemistry profiles, urinalysis, urinary protein-to-creatinine ratio, and estimated or measured glomerular filtration rate (GFR). Serial estimated GFR (eGFR) values over time can be used to derive an eGFR slope, which can document the rate of kidney function decline. (See "Assessment of kidney function" and "Calculation of the creatinine clearance".)

●Echocardiography and electrocardiography to detect and monitor cardiac abnormalities should be performed at least every two years. Cardiac MRI may be required to assess fibrotic lesions in patients with or without overt LVH and is preferred in females for whom myocardial fibrosis may precede the develop of LVH. (See 'Initial assessment' above.)

●Asymptomatic female carriers should also have a complete baseline evaluation as above and should be initially reevaluated every three to five years, with increasing frequency with increasing age. Atypical males with Fabry disease should be evaluated and monitored annually similar to those classically affected.

DIFFERENTIAL DIAGNOSIS — Fabry disease is often misdiagnosed, given its wide range of nonspecific clinical manifestations and relative rarity. It has recently been termed "The New Great Imposter" [130]. Because of its rarity, patients with Fabry disease are often initially diagnosed with another condition. Initially considered diagnoses in patients with Fabry disease in the Fabry Outcome Survey included the following [5,6]:

●Rheumatologic conditions including dermatomyositis or rheumatic fever – However, the characteristic heliotrope rash and elevated serum muscle enzymes distinguish juvenile-onset dermatomyositis from Fabry disease. In addition, the pain and dermatologic symptoms of acute rheumatic fever are typically self-limited, lasting less than a month. (See "Juvenile dermatomyositis and other idiopathic inflammatory myopathies: Diagnosis" and "Acute rheumatic fever: Clinical manifestations and diagnosis".)

●Arthritis – However, Fabry disease is not characterized by synovial inflammation. (See "Diagnosis and differential diagnosis of rheumatoid arthritis".)

●Neuropsychological disease – However, many common manifestations of Fabry, including proteinuria, left ventricular hypertrophy (LVH), neuropathic pain (acroparesthesias), and angiokeratomas, are not typical in patients with psychiatric disease. (See "Fabry disease: Neurologic manifestations".)

●Fibromyalgia – As above, many common manifestations of Fabry, including proteinuria, LVH, and angiokeratomas, are not common in patients with fibromyalgia. (See "Clinical manifestations and diagnosis of fibromyalgia in adults".)

●Erythromelalgia – This causes burning pain and swelling in the hands and feet. Pain in the extremities can also be caused by polycythemia vera and essential thrombocythemia, but blood cell counts are generally normal in Fabry disease, until patients develop anemia associated with chronic kidney disease (CKD). (See "Clinical manifestations and diagnosis of polycythemia vera", section on 'Erythromelalgia'.)

●Hereditary hemorrhagic telangiectasia – Although patients with Fabry disease may have telangiectasias, they do not typically develop spontaneous epistaxis or gastrointestinal bleeding, as do patients with hereditary hemorrhagic telangiectasia. (See "Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)".)

●Meniere disease – Although tinnitus is present in nearly 40 percent of patients with Fabry disease, the presence of neuropathic pain, angiokeratomas, and proteinuria help distinguish it from Meniere disease. (See "Meniere disease: Evaluation, diagnosis, and management".)

●Multiple sclerosis – However, the presence of angiokeratomas, proteinuria, and LVH, which are not features of multiple sclerosis, provide clues to Fabry disease. (See "Manifestations of multiple sclerosis in adults".)

●Irritable colon – However, neuropathic pain, angiokeratomas, and proteinuria are not features of irritable bowel syndrome.

●Idiopathic hypertrophic cardiomyopathy – Echocardiography may be able to distinguish patients with Fabry disease from those with other causes of LVH. (See "Fabry disease: Cardiovascular disease".)

●Kidney failure of unknown etiology – When occurring in a young individual, kidney disease of unknown etiology should prompt an evaluation for Fabry disease, particularly if other common manifestations (eg, neuropathic pain) and a family history of kidney failure are present. (See 'When to suspect Fabry disease' above.)

As a result, the diagnosis of Fabry disease in patients without a known family history of the disorder is usually made by specialists and subspecialists: dermatologists (28 percent), neurologists (23 percent), nephrologists (19 percent), rheumatologists (2 percent), and cardiologists (2 percent) [3]. Consideration of Fabry disease as a possibility is the major hurdle to making the correct diagnosis in such patients. The increase in testing for genetic diseases with newborn screening and targeted gene panels may improve diagnosis substantially.

SCREENING FAMILY MEMBERS — In families known to have Fabry disease, we suggest the following approach in individuals at risk [89]:

●At-risk or symptomatic male relatives of an affected individual – These males should be screened with an enzymatic assay (blood or leukocyte) or genetic testing, even if asymptomatic.

●At-risk female relatives of an affected individual, a female with a family history of Fabry disease, or a female with symptoms suggestive of Fabry disease – When testing females, sequencing the GLA gene is the diagnostic test of choice. Alpha-galactosidase A (Alpha-Gal A) activity should not be used to diagnose females, given the high false-negative rate of alpha-Gal A testing among female carriers [17,32,119].

Although becoming increasingly available and even mandated at a state-wide level in some areas, routine neonatal screening poses special challenges as many GLA variants found are of unknown clinical significance and there are no data to suggest efficacy of initiating available therapy during infancy [89]. However, every positive result indicating a pathogenic gene defect provides an entire family to be assessed, even with late-onset, non-classical GLA variants [17].

Prenatal testing involves measuring alpha-Gal A activity in fetal cells obtained through amniocentesis or chorionic villous sampling; the latter allows earlier (9 versus 16 weeks) and faster test results (hours versus two weeks). However, a genetic mutation analysis must also be done because the sample may be contaminated with maternal tissue or, alternatively, female fetuses may have variable residual enzymatic activity. The issues surrounding prenatal testing and by inference gamete or zygote selection are even more challenging than neonatal screening.

Some have advocated screening by testing for elevated urinary excretion of globotriaosylceramide (Gb3). Mass spectrometry is one available method, with abnormally high levels being compared with healthy controls tested in the same laboratory [131,132]. However, urine Gb3 and globotriaosylsphingosine (lysoGb3) may not always be elevated in heterozygotes or male patients with mild disease. In addition, urine Gb3 levels may be elevated in patients with common forms of heart disease who do not have Fabry disease [103,133]. (See 'Gb3 and lysoGb3 levels' above.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Fabry disease" and "Society guideline links: Chronic kidney disease in adults".)

SUMMARY AND RECOMMENDATIONS

●General principles – Fabry disease, also called Anderson-Fabry disease, is an X-linked inborn error of the glycosphingolipid metabolic pathway. The metabolic defect in Fabry disease is a deficiency or defect in the lysosomal hydrolase alpha-galactosidase A (alpha-Gal A), which catalyzes the hydrolytic cleavage of the terminal galactose from globotriaosylceramide (Gb3). This results in accumulation of Gb3 predominantly within cells, including in lysosomes, and the potential pathogenic effects of the deacylated derivative globotriaosylsphingosine analogues (lysoGb3s) in a wide variety of cells, producing the many manifestations of the disease. (See 'Introduction' above and 'Pathophysiology' above.)

●Genetics – Fabry disease is caused by pathogenic variants in the alpha-Gal A (galactosidase alpha [GLA]) gene mapped to the long arm (Xq22.1 region) of the X chromosome and is inherited as an X-linked disorder. In general, hemizygous males are more severely affected than females. Female heterozygotes have a variable disease course that ranges from asymptomatic disease to a more severe phenotype that resembles that seen in males. This phenotypic variation is due in part to skewed X-chromosome inactivation. (See 'Genetics' above.)

●Clinical presentation – Patients with Fabry disease may present with a spectrum of clinical manifestations, ranging from the severe classic phenotype in males to asymptomatic disease in some females, with a variety of clinical presentations in between (table 1). The age of symptom onset is more consistent in male hemizygotes with a classic presentation than in female heterozygotes; approximately 80 percent of males with classic disease have neurologic, dermatologic, and kidney and cardiac manifestations by the second, third, and fifth decades of life, respectively. Males with atypical variants often present later in life, diagnosed during evaluations for cardiomegaly, proteinuria or chronic kidney disease (CKD), or stroke. (See 'Clinical presentation' above.)

●Diagnosis

•Initial assessment – The initial evaluation of patients suspected of Fabry disease should consist of a detailed medical history and physical examination looking for suggestive clinical symptoms; a family history of unexplained neurologic, kidney, or cardiac disease transmitted in an X-linked pattern; angiokeratomas; telangiectasias; hypohidrosis; corneal opacities; and an abnormal cardiac examination. Laboratory studies should include urinalysis, quantitative assessment of proteinuria and kidney function, and an electrocardiogram. Some clinicians obtain baseline magnetic resonance imaging (MRI) of the heart and brain as part of the initial evaluation, particularly in females and patients who present with cardiac or neurologic manifestations. (See 'Initial assessment' above.)

•Establishing the diagnosis – In the setting of clearly established family history and classic phenotype, the diagnosis can be confirmed in males by a low alpha-Gal A activity in leukocytes (or plasma) (algorithm 1). Mutation analysis of the GLA gene is required to make the diagnosis in males and females and in patients with atypical presentations or who have residual alpha-Gal A levels. The diagnosis of Fabry disease is typically established with a combination of biochemical and molecular genetic testing and/or by family history, although incidental findings on kidney or cardiac biopsies and typical skin and/or eye findings may also lead to the diagnosis. Definitive confirmation of the diagnosis requires genetic determination of the GLA variant. (See 'Establishing the diagnosis' above.)

●Screening family members – In families known to have Fabry disease, we suggest screening at-risk or symptomatic male relatives of an affected individual, at-risk female relatives of an affected individual, females with a family history of Fabry disease, and females with symptoms suggestive of Fabry disease. (See 'Screening family members' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Jeffrey Kopp, MD, who contributed to earlier versions of this topic review.