Fabry Disease

Molecular Testing

Molecular testing approaches can include single-gene testing, use of a multigene panel, and more comprehensive genomic testing:

• Single-gene testing. Sequence analysis of GLA is performed first and followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found.
  Targeted analysis for the p.Ala143Pro pathogenic variant can be performed first in individuals from Nova Scotia (incidence 1:15,000).
  Targeted analysis for the IVS4+919G>A pathogenic variant can be performed first in individuals of Chinese ancestry with atypical presentation (see Molecular Genetics) [Liu et al].
• A multigene panel that includes GLA and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
• More comprehensive genomic testing may be considered if single-gene testing (and/or use of a multigene panel) has not confirmed a diagnosis in an individual with features of Fabry disease. Such testing may include exome sequencing, genome sequencing, and mitochondrial sequencing.
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Additional Testing

Biomarkers

• Plasma globotriaosylsphingosine (lyso-Gb3) (the lyso derivative of the accumulated substrate) levels appear to correlate with disease severity and to decline with enzyme replacement therapy [Aerts et al 2008].
• Urinary levels of lyso-Gb3 derivatives also correlate with disease severity [Auray-Blais et al 2015].
• Plasma lyso-Gb3 levels are higher in affected males than females.
• Identification of elevated plasma and urinary lyso-Gb3 can confirm the diagnosis in an individual with a GLA variant of uncertain significance identified by molecular genetic testing or late-onset disease manifestations. Niemann et al [2014] reported that individuals with a novel variant and organ involvement consistent with Fabry disease had lyso-Gb3 levels ≥2.7ng/mL; Individuals with a novel GLA variant and no organ involvement had lyso-Gb3 levels <2.7 ng/mL.

Note: There are no universally recognized biomarkers of Fabry disease.

Endomyocardial biopsy. Identification of characteristic globotriaosylceramide (GL-3) inclusions on endomyocardial biopsy can establish a diagnosis in an individual with left ventricular hypertrophy and a GLA variant of uncertain significance [Hsu et al 2014].

Classic Fabry Disease

Onset of symptoms usually occurs in childhood or adolescence with the appearance of angiokeratomas, periodic crises of severe pain in the extremities (acroparesthesia), hypohidrosis, and the characteristic corneal and lenticular opacities. Although proteinuria may be detected early, renal insufficiency usually occurs in the third to fifth decade of life. Death occurs from complications of renal disease, cardiac involvement, and/or cerebrovascular disease.

Angiokeratomas are often one of the earliest manifestations of Fabry disease. They appear as clusters of punctate, dark red to blue-black angiectases in the superficial layers of the skin. The lesions may be flat or slightly raised and do not blanch with pressure. Slight hyperkeratosis is notable in larger lesions.

The clusters of lesions are most dense between the umbilicus and the knees; they most commonly involve the hips, back, thighs, buttocks, penis, and scrotum, and tend to be bilaterally symmetric. The oral mucosa, conjunctiva, and other mucosal areas are commonly involved. A wide variation in the distribution pattern and density of the lesions may occur. Examination of the skin, especially the scrotum and umbilicus, may reveal the presence of isolated lesions. Data from 714 affected individuals (345 males, 369 females) in the FOS [Orteu et al 2007] suggest that they are present in 66% of males (36% of females).

The number and size of these cutaneous vascular lesions progressively increase with age. The presence of angiokeratoma correlated with the severity of the systemic disease manifestations [Zampetti et al 2012].

Acroparesthesia occurs as episodic crises of agonizing, burning pain in the distal extremities that most often begin in childhood or early adolescence and signal clinical onset of the disease. These crises last from minutes to several days and are usually triggered by exercise, fatigue, emotional stress, or rapid changes in temperature and humidity. Often the pain radiates to the proximal extremities and other parts of the body. Attacks of abdominal or flank pain may simulate appendicitis or renal colic.

The crises usually decrease in frequency and severity with increasing age; however, in some affected individuals, the frequency increases and the pain can be so excruciating and incapacitating that the individual may contemplate suicide.

Hypohidrosis or anhidrosis is an early and almost constant finding. Hyperhidrosis also occurs; in the FOS it was seen in 12% of females and 6.4% of males [Lidove et al 2006].

Cornea verticillata, the characteristic corneal opacity that is observed only by slit-lamp microscopy, is found in affected males and most heterozygous females. The earliest corneal lesion is a diffuse haziness in the subepithelial layer. With time, the opacities appear as whorled streaks extending from a central vortex to the periphery of the cornea. The whorl-like opacities, typically inferior and cream colored, range from white to golden brown and may be very faint [Nguyen et al 2005]. In the FOS, cornea verticillata was present in 77% of females and 73% of males undergoing detailed ophthalmologic examination [Sodi et al 2007].

Lenticular changes are present in approximately 30% of affected males and include a granular anterior capsular or subcapsular deposit and a unique, possibly pathognomonic, lenticular opacity (the "Fabry cataract"). The cataracts, which are best observed through a dilated pupil by slit-lamp examination using retroillumination, are whitish, spoke-like deposits of fine granular material on or near the posterior lens capsule. These lines usually radiate from the central part of the posterior cortex. The corneal and lenticular opacities do not interfere with visual acuity.

Other ocular features. Aneurysmal dilatation and tortuosity of conjunctival and retinal vessels also occur; while not specific for Fabry disease, vessel tortuosity is observed more frequently in individuals with a higher disease severity score [Sodi et al 2007, Allen et al 2010]. Data from the FOS demonstrates that the ocular changes correlate well with overall disease severity and with genotype [Pitz et al 2015].

Cardiac disease. Mitral insufficiency may be present in childhood or adolescence. Left ventricular enlargement and conduction abnormalities are early findings. Left ventricular hypertrophy, often associated with hypertrophy of the interventricular septum and appearing similar to hypertrophic cardiomyopathy (HCM), is progressive and occurs earlier in males than females [Kampmann et al 2005]. Cardiac disease is present in most males with the classic phenotype by middle age and is the major cause of morbidity and mortality in those who have undergone dialysis or transplantation for treatment of end-stage renal disease (ESRD).

ECG changes including ST segment changes, T-wave inversion, and dysrhythmias such as a short PR interval and intermittent supraventricular tachycardias may be caused by infiltration of the conduction system. Echocardiography demonstrates an increased thickness of the interventricular septum and the left ventricular posterior wall [Pieroni et al 2006]. Magnetic resonance studies using gadolinium demonstrated late enhancement areas, corresponding to myocardial fibrosis and associated with decreased regional functioning as assessed by strain and strain-rate imaging [Moon et al 2003, Weidemann et al 2005]. T₁ mapping illustrates intramural fat deposition and posterior wall fibrosis [Sado et al 2013].

Among 714 predominantly adult individuals in the FOS [Linhart et al 2007], angina, palpitations/arrhythmia, and exertional dyspnea were found in 23%-27% of males and 22%-25% of females. Hypertension, angina pectoris, myocardial ischemia and infarction, congestive heart failure, and severe mitral regurgitation are late signs. Hypertension was found in more than 50% of males and more than 40% of females in the FOS [Kleinert et al 2006].

Cerebrovascular manifestations result primarily from multifocal small vessel involvement and may include thrombosis, transient ischemic attacks (TIA), basilar artery ischemia and aneurysm, seizures, hemiplegia, hemianesthesia, aphasia, labyrinthine disorders, or frank cerebral hemorrhage [Politei & Capizzano 2006]. FOS data indicate that stroke or TIA occur in approximately 13% of affected individuals overall (15% males, 11.5% females) [Ginsberg et al 2006]. The Fabry Registry has reported that cerebrovascular manifestations are often a presenting feature of Fabry disease and may be more frequent than previously recognized [Sims et al 2009]. Rolfs et al [2005] reported that in Germany a GLA pathogenic variant was identified in 21 of 432 males (4.9%) and seven of 289 females (2.4%) age 18-55 years suffering cryptogenic stroke. However, other studies have not confirmed such a high prevalence [Brouns et al 2010, Wozniak et al 2010, Rolfs et al 2013]. Thromboembolic events are more common among individuals with Fabry disease who also have the factor V Leiden variant [Lenders et al 2015].

In addition, a distinct neurologic phenotype including decreased motor performance and nonmotor neurologic manifestations has been described. Individuals with Fabry disease showed slower gait and transfer speed, poorer fine manual dexterity, and slower hand speed than controls. Affected individuals had an increased incidence of depression, pain, and daytime sleepiness but did not exhibit extrapyramidal motor features or signs of significant cognitive impairment [Löhle et al 2015].

Renal involvement. Progressive glycosphingolipid accumulation in the kidney interferes with renal function, resulting in azotemia and renal insufficiency.

During childhood and adolescence, protein, casts, red cells, and birefringent lipid globules with characteristic "Maltese crosses" can be observed in the urinary sediment. Proteinuria, isosthenuria, and a gradual deterioration of tubular reabsorption, secretion, and excretion occur with advancing age. Polyuria and a syndrome similar to vasopressin-resistant diabetes insipidus occasionally develop.

Gradual deterioration of renal function and the development of azotemia usually occur in the third to fifth decade of life, although ESRD has been reported in the second decade. Death most often results from ESRD unless chronic hemodialysis or renal transplantation is undertaken. The mean age at death of males not treated for ESRD is 41 years, but occasionally an untreated male with the classic phenotype survives into the seventh decade.

Other clinical features. In addition to the major clinical features described above, males and females with the classic phenotype may have gastrointestinal, auditory, pulmonary, and other manifestations.

• Gastrointestinal. Glycosphingolipid deposition in intestinal small vessels and in the autonomic ganglia of the bowel may cause episodic diarrhea, nausea, vomiting, bloating, cramping abdominal pain, and/or intestinal malabsorption [Hoffmann et al 2007]. Achalasia and jejunal diverticulosis, which may lead to perforation of the small bowel, have been described. Radiographic studies may reveal thickened, edematous colonic folds, mild dilatation of the small bowel, a granular-appearing ileum, and the loss of haustral markings throughout the colon.
• Pulmonary. Several affected individuals have had pulmonary involvement, manifest clinically as chronic bronchitis, wheezing, or dyspnea. Primary pulmonary involvement has been reported in the absence of cardiac or renal disease. Pulmonary function studies may show an obstructive component [Magage et al 2007] which has been demonstrated to stabilize with enzyme replacement therapy (ERT) [Odler et al 2017].
• Vascular. Pitting edema of the lower extremities may be present in adulthood in the absence of hypoproteinemia, varices, or other clinically significant vascular disease. Although the pitting edema is initially reversible, progressive glycosphingolipid deposition in the lymphatic vessels and lymph nodes results in irreversible lymphedema requiring treatment with compression hosiery. Varicosities, hemorrhoids, and priapism have also been reported.
• Cranial nerve VIII involvement. High-frequency hearing loss, tinnitus, and dizziness have been reported [Hegemann et al 2006].
• Psychological. Depression, anxiety, severe fatigue, and other psychosocial manifestations lead to decreased quality of life in many affected individuals [Cole et al 2007].

Heterozygous (Carrier) Females

The clinical manifestations in heterozygous females range from asymptomatic throughout a normal life span to as severe as affected males. Variation in clinical manifestations is attributed to random X-chromosome inactivation [Deegan et al 2006]. More severely affected females are more likely to express the X chromosome with the GLA pathogenic variant in affected organs [Echevarria et al 2016].

Most heterozygous females from families in which affected males have the classic phenotype have a milder clinical course and better prognosis than affected males.

Mild manifestations include the characteristic cornea verticillata (70%-90%) and lenticular opacities that do not impair vision; acroparesthesia (50%-90%); angiokeratomas (10%-50%) that are usually isolated or sparse; and hypohidrosis. In addition, heterozygotes may have chronic abdominal pain and diarrhea [Gupta et al 2005].

With advancing age, heterozygotes may develop mild to moderate enlargement of the left heart (left ventricular hypertrophy) and valvular disease. More serious manifestations include significant left ventricular hypertrophy, cardiomegaly, myocardial ischemia, infarction, and cardiac arrhythmias [Shah et al 2005, Deegan et al 2006, Wilcox et al 2008].

The occurrence of cerebrovascular disease including transient ischemic attacks and cerebrovascular accidents is consistent with the microvascular pathology of the disease [MacDermot et al 2001, Whybra et al 2001, Galanos et al 2002].

Renal findings in heterozygotes include isosthenuria, the presence of erythrocytes, leukocytes, and granular and hyaline casts in the urinary sediment, and proteinuria. According to the United States and European dialysis and transplantation registries, approximately 10% of heterozygotes develop renal failure requiring dialysis or transplantation.

Excessive guilt, fatigue, occupational difficulty, suicidal ideation, and depression have been noted in heterozygotes [Sadek et al 2004].

Life expectancy and cause of death. Based on data from the Fabry Registry, 75 of 1422 males and 12 of 1426 females were reported to have died. The 87 deceased individuals were diagnosed at a much older age than other individuals in the Fabry Registry. The life expectancy of males with Fabry disease was 58.2 years, compared with 74.7 years in the general population of the United States. The life expectancy of females with Fabry disease was 75.4 years, compared with 80.0 years in the United States general population. The most common cause of death among both genders was cardiovascular disease [Waldek et al 2009]. Most individuals (57%) who died of cardiovascular disease had previously received renal replacement therapy (e.g., dialysis or transplantation). In the FOS, the principal causes of death among 181 affected relatives (most of whom had died before 2001) were renal failure in males (42%) and cerebrovascular disease in females (25%) [Mehta et al 2009]. In contrast, of the 42 individuals enrolled in the FOS whose deaths were reported between 2001 and 2007, cardiac disease was the main cause of death in both males (34%) and females (57%). The possible impact of ERT on life expectancy is discussed in Management, Prevention of Primary Manifestations.

Atypical Variants of Fabry Disease

Cardiac variant. Males and females with cardiac disease are asymptomatic during most of their lives and typically present in the sixth to eighth decade of life with left ventricular hypertrophy, hypertrophic cardiomyopathy (HCM), conduction disturbances and arrhythmias. Screening of males with "late-onset" hypertrophic cardiomyopathy (HCM) found that 6.3% who were diagnosed at or after age 40 years and 1.4% of males who were diagnosed before age 40 years had Fabry disease confirmed by identification of low α-Gal A enzyme activity and a GLA hemizygous pathogenic variant [Sachdev et al 2002]. Magnetic resonance imaging of the heart typically shows late enhancement of the posterior wall with gadolinium reflecting posterior wall fibrosis demonstrated in postmortem specimens [Moon et al 2003]. The incidence of cardiac complications is similar in individuals with the atypical Fabry cardiac variant and individuals with classic Fabry disease [Patel et la 2015].

Individuals with the cardiac variant exhibit mild to moderate proteinuria with normal renal function for age. Renal pathology is limited to glycosphingolipid deposition in podocytes, which is presumably responsible for their proteinuria. They generally do not develop renal failure.

Renal variant. Renal variants were identified among individuals of Japanese ancestry on chronic hemodialysis in whom ESRD had been misdiagnosed as chronic glomerulonephritis [Nakao et al 2003]. Of note, five of the six individuals did not have angiokeratoma, acroparesthesia, hypohidrosis, or corneal opacities, but did have moderate to severe left ventricular hypertrophy. These observations indicated that the early symptoms of classic Fabry disease may not occur in individuals with the renal variant who develop renal insufficiency, and that the renal variant may be underdiagnosed. Therefore, it is appropriate to test individuals on renal dialysis and/or undergoing renal transplantation without a confirmed etiology of renal disease for Fabry disease.