Review article

Fabry Disease

Often Seen, Rarely Diagnosed

Dtsch Arztebl Int 2009; 106(26): 440-7. DOI: 10.3238/arztebl.2009.0440

Hoffmann, B; Mayatepek, E

Background: Data obtained from screened newborns and from persons at known risk for Fabry disease suggest that this condition is much more common in Germany than previously assumed. Its clinical manifestations are very diverse, and its differential diagnosis is correspondingly broad. Thus, there is often a delay before the diagnosis of Fabry disease is established.
Methods: Selective literature search with special attention to studies of large groups of patients with respect to clinical manifestations, diagnostic evaluation, and treatment.
Results: The number of patients carrying the diagnosis of Fabry disease in Germany lies far below what would be expected from published prevalence figures from other countries. Angiokeratoma, acroparesthesia, hypertrophic cardiomyopathy, impaired sweating and corneal opacification (cornea verticillata) are typical manifestations of Fabry disease; many patients also have other, nonspecific complaints, such as gastrointestinal disturbances. It has been clearly shown that women can manifest the entire range of clinical manifestations. Studies involving large groups of patients have improved our understanding of hearing impairment and tinnitus in Fabry disease. Therapeutic trials are currently in progress to determine whether enzyme substitution can delay the occurrence of life-threatening sequelae such as progressive renal failure and cerebrovascular events.
Conclusions: Fabry disease is still underdiagnosed. The average delay from the onset of symptoms to diagnosis is more than a decade. Treatment with human alpha-galactosidase A produced with genetic technology can improve most of the disease's manifestations.
Dtsch Arztebl Int 2009; 106(26): 440–7
DOI: 10.3238/arztebl.2009.0440
Key words: lysosomal storage disease, Fabry disease, enzyme substitution, molecular medicine, diagnosis
LNSLNS Lysosomes are membrane bound organelles that contain 50 to 60 acid hydrolases and constitute a kind of cellular digestive tract. If one of these enzymes is missing, the lysosomal metabolism is interrupted and certain metabolites accumulate. Diseases that are due to a lysosomal enzyme deficiency are known as lysosomal storage diseases. Since lysosomes are present in most cells in the body, storage diseases manifest as multisystem pathologies.

One of the storage diseases is Fabry disease, which is due to X-linked, inherited alpha-galactosidase A deficiency (e1). As a result of the enzyme deficiency, the sphingolipid globotriaosylceramide (Gb3) accumulates in the lyosomes. Fabry disease is still regarded as a rare disease. However, studies of risk groups and prospective data collections from neonatal screening imply a much higher prevalence than hitherto assumed (Table 1 gif ppt). The reasons for the substantial variations in the prevalence rates are complex. The clinical course of Fabry disease is heterogeneous and variable, especially in women. The range of possible differential diagnoses is broad and may touch many medical subspecialties (Table 2 gif ppt). The risk of a delayed or incorrect diagnosis is correspondingly high. The time period from symptom onset to the correct diagnosis is long: 13 years in men and 17 years in women (e7).

This review article shows the clinical diversity of Fabry disease and draws attention to this underdiagnosed and often forgotten pathology. A diagnostic algorithm is presented, as is an overview of therapeutic options.

We conducted a selective literature review, which took into account especially recent studies that describe results from larger patient cohorts or present completely new aspects of pathophysiology, clinical presentation, or treatment.

Clinical picture
The Box (gif ppt) shows an overview of the range of possible complaints.

Skin
In children, the classic angiokeratoma (Figure 1 jpg ppt) is found in only about 30% of those younger than 16. In adults, however, the pinhead sized, mostly singly positioned, reddish-brownish efflorescences (2) are seen in two thirds of male patients and more than a third of female patients. The diagnosis is, however, rarely made by a dermatologist (2). Typical locations are the fingertips, the bathing trunk area, the buttocks, and the periumbilical area, but angiokeratoma can also occur on the mucosa—for example, in the gastrointestinal tract (e8). Further skin manifestations are teleangiectasias, lymphedema, and sweating disturbances. In most cases, hypohidrosis is present (in 53% of men and 28% of women); more rarely, hyperhidrosis or anhidrosis (total absence of sweat secretion) (2). Another indication of Fabry disease may be intolerance to rising environmental temperatures.

The cause is apparently impaired sympathetic innervation of the skin, as well as dysfunction of the sweat glands from deposition of storage material. The development of lymphedema is accompanied by obliteration, vascular ectasias, and/or increased permeability of the lymphatic vessels (e10, e12).

Pain
Male patients tend to experience acute, mostly burning, pain from the 14th year of life, and women from the age of 19 (3). Altogether, more than 70% of patients experience pain (3). In addition to the usual acroparesthesias, any region of the body may be affected. Some 15% to 30% of patients complain about neck pain and headache, and it is not always possible to distinguish such headaches from migraine or cluster headaches because imaging methods usually do not help to explain the pain. Physical activity, rising environmental or body temperatures, and concomitant illnesses may trigger pain crises. Foods such as coffee, meat, and alcohol may trigger pain, as can psychological stress. Not only acute pain, but also chronic neuropathic pain may develop.

The pain and disrupted sensation of vibration and temperature are due to stored sphingolipids in the dermal axons, which are mainly located in the thin myelinated A-δ fibers (e13).

Gastrointestinal symptoms
More than 50% of patients report gastrointestinal symptoms (4). Up to 50% of patients with Fabry disease complain of abdominal pain. The average age at which these symptoms manifest is 14 (4), which is also the age at which acroparesthesias set in (3). Both forms of pain manifestation are accompanied by the same histological changes to the neurons. Patients usually report switches from diarrhea to constipation, which may mimic irritable bowel syndrome (e14). No inflammatory changes are present; the symptoms are due to intestinal neuropathy with storage material on the smooth muscle cells, endothelial cells, and ganglial cells (e8). Meissner's plexuses are vacuolized (e15). The result may be an early sensation of satiety and delayed intestinal passage (e8, e15, e16).

Eyes
Corneal opacities (corneal verticillata) have been described as almost pathognomonic for Fabry disease. As a rule, these changes do not lead to impaired vision (e17, e18). They occur in 75% of women and up to 90% of men with Fabry disease (5, e18). Corresponding corneal changes can be seen prenatally (e19) and are usually easy to detect in the ophthalmological examination using a slit lamp. In addition to treatment with amiodarone, Fabry disease is the most common cause of this form of corneal opacity (e20), and taking a simple medication history often helps clarify the cause.

Independently of corneal changes, up to 75% of men and 20% of women with Fabry disease develop tortuous retinal vessels (tortuositas vasorum) (5, e18). Corresponding changes have even been observed in infants and apparently become more frequent with age (5). Rarer ophthalmological symptoms include uveitis (e21, e22), closure of the central artery (e23), and aneurysmatic vessels in the conjunctiva (e18, e24).

Ears
Sensorineural hearing loss seems to be the most important ear manifestation of Fabry disease. Prevalence rates of acute hearing loss in Fabry disease, which develops within a few hours to days and is initially often reversible, range from 5% to 30% (6, 7, e25). Acute hearing loss is thus 60 times more common in Fabry disease than in the normal population; it affects twice as many men as women (7). Most patients experience slowly progressive hearing loss that permanently affects both ears and all frequencies (6, 7, e28). Onset of hearing loss is in the second decade of life in men and in the fourth decade in women. Hearing loss for higher frequencies develops more rapidly than for the lower frequencies (7). Remarkably, more than a third of patients in whom audiometric tests have shown hearing loss do not report any problems (7). Almost two thirds of women, but only slightly more than 40% of men, with Fabry disease experience tinnitus (6). Independently of the hearing loss or tinnitus, most patients with Fabry disease have damaged auditive functioning of the ear as well as a damaged vestibular organ (8). The most likely cause of the acute hearing loss are microvascular events (8). Chronic hearing loss, however, is usually the result of Gb3 accumulation in the audiovestibular ganglia and vessels of the cochlea and is therefore termed sensorineural (e26).

Progressive renal failure, cardiomyopathy, and myocardial infarction, as well as transient ischemic attacks (TIAs) and strokes reduce the survival time for male, untreated patients with Fabry disease to an average of 55 years, for women to 70 years (9).

Cardiovascular system
On average, more than 50% of patients with Fabry disease have cardiac symptoms at the age of 36 (10). Some 33% of women and more than 50% of men with Fabry disease—more with advancing age—who do not receive treatment develop progressive left ventricular hypertrophy (LVH). Conversely, a secondary screening study for left ventricular cardiomyopathy identified Fabry disease in 15 of 508 patients (11). In addition to cardiomyopathy, other cardiac symptoms are common, such as a shortened PR interval, a negative T wave, and a high amplitude. Up to 20% of male and female patients experience cardiac arrhythmias (10, e27); this may also affect children (10). Clinically relevant valvular disorders are present in 15% of patients (12). In spite of the relative frequency of problems associated with angina pectoris, patients with Fabry disease rarely experience myocardial infarctions due to stenosis (e28). Cardiac symptoms do not manifest only in adults but also affect children and adolescents. Manifest left ventricular hypertrophy was found in 7 out of 20 children; the remaining patients had a left ventricular mass above the 75th percentile of healthy children (12). Left ventricular functional disorders can be detected before the myocardium thickens (e29). In childhood, impaired variability of heart frequency may be observed, which is indicative of involvement of the parasympathetic and sympathetic nervous system (12).

Pathophysiologically, storage of Gb3 in myocardial cells, cells of the conduction system (e30), and smaller coronary vessels has been found (e31).

Kidneys
Proteinuria is regarded as the earliest sign of clinically relevant renal involvement in Fabry disease; it is found in 10% of all children younger than 18 years who have Fabry disease. In individual cases, this may occur at the age of 2 years (14). At age 35 it is present in about half of male patients. By age 47, half of all untreated male patients with Fabry disease have developed terminal renal failure. Similar data are also available for female patients (e28), and in individual cases, renal failure develops in adolescence (15). Macroscopic changes to the kidneys are seen in 50% of adults with Fabry disease—for example, as renal cysts—and their prevalence seems to increase with age (e33, e34).The cause of renal failure in Fabry disease is glomerular damage (14, 15). Renal biopsies in children have shown that lipid storage in podocytes and glomerular, interstitial, or vascular changes develop even before clinical renal functional impairment occurs (14).

Central nervous system
The most severe neurological complications in Fabry disease are TIA and (ischemic) stroke. Almost 25% of patients experience a cerebrovascular event over the course of their disease (mean age in men, 34 years; in women, 54 years) (16). Clinical precursors may be hearing loss, dizziness, migraine, and diplopic images. It must be born in mind that not only are patients with Fabry's disease at increased risk of stroke, but that Fabry's disease must be excluded as a possible cause in any patient aged under 55 who suffers a stroke (17).

In 50% of patients aged 33 to 47 years, the central nervous system shows unspecific changes in the form of white matter lesions, in half of these in combination with gray matter lesions (e35). Pathophysiologically, CNS areas with white matter lesions have a lower cerebral glucose metabolism than areas without such changes. There are also indications that the white matter lesions are caused by an imbalance of regional cerebral blood circulation and glucose metabolism (e36). A recent study has shown 87% precision for cranial MR-angiography of the basiliar artery with an increased diameter, which helps distinguish patients with Fabry disease from their peers of the same age (Fellgiebel et al. Neurology 2009; 72: 63–8).

Other complaints
A multisystem disease that is accompanied by chronic pain, that has a far too long diagnostic latency period, and that is associated with a substantially lower life expectancy is necessarily also accompanied by an increased risk of depression (e37). The quality of life of untreated patients with Fabry disease is obviously greatly reduced compared with the normal population (e38).

Diagnosis
A suspected diagnosis of Fabry disease has to be deduced from the individual clinical picture. This is crucial for affected patients; the range of possible differential diagnoses is wide (Table 2). In case of doubt, Fabry disease should be included in the range of possible diagnoses that need clarifying in all patients with atypical clinical courses, uncertain diagnoses, or an unclear clinical picture.

It should be noted that measuring enzyme activity—in affected men, typically <1%—often yields false positive or false negative results in women. The randomized X inactivation is responsible for this; as a result of this, the healthy or faulty GLA gene is switched on or off in each cell, independently of each other and at random. Women with suspected Fabry disease therefore need to undergo a molecular genetic examination with complete sequencing of the GLA gene. Such an examination costs from 70 euros. In principle, histopathological diagnostic tests are possible, but these have been rendered less important by the relatively simple enzyme tests and molecular diagnosis. A diagnostic flow chart for patients with Fabry disease is shown in Figure 2 (gif ppt). Additionally, prenatal diagnosis is possible, especially by using chorionic villus sampling (e39). After the diagnosis has been made, patients should immediately be referred to human genetic counseling.

Treatment and conclusions
Since 2001, two preparations have been licensed for the causal treatment of Fabry disease in the European Union. Both gene technologically produced alpha-galactosidase A variants are based on human DNA, but they are produced in different ways and have different glycosylation patterns (e40). The treatment is entirely safe; both preparations are administered as infusions every fortnight (22, 23). Differences exist with respect to dosage (0.2 mg/kg for agalsidase alfa and 1.0 mg/kg for agalsidase beta) and infusion time (40 minutes independent of body weight for agalsidase alfa and 15 mg/h for agalsidase beta). Especially in the first 3 months of treatment, adverse medication effects may occur, which should be classed primarily as allergic reactions. Further to headaches, hot flushes, and a raised temperature, patients may develop nausea and vomiting, flushing, and chills. After primary treatment of these problems (stopping the infusion; glucocorticoids, H1-receptor blockers, and, if required, H2-receptor blockers), the infusion can, in all experience, be continued.

The therapy has to be continued for a patient's entire lifetime; the costs are substantial, amounting to 250 000 euros per patient per year, and are independent of which of the two preparations patients choose after receiving comprehensive information. Since this is the only causal therapeutic option for Fabry disease, the German health insurers cover the costs, and the prescription and administration of the therapy are classed as an additional position that does not affect the practice's drug budget.

Table 3 (gif ppt) provides an overview of the positive effects of enzyme replacement therapy as described thus far. To enable better understanding, we classified the references by type of study design. Obviously, it has been possible for only very few studies to be conducted in a double blind, randomized, and controlled fashion, as patients with a known diagnosis of Fabry disease were given causal therapy after the preparations had become licensed. The available information about the long term treatment with enzyme replacement therefore comes mostly from cohort studies that were developed from the two available patient registries, or from open extension studies of the phase III trials. Nonetheless, it is clear that patients with Fabry disease benefit from enzyme replacement. Further to an improved quality of life, the function of the vital organs improved significantly, or the progression of the disease was halted. However, even 8 years after enzyme replacement therapy for Fabry disease has been introduced, many therapeutic questions remain unanswered—for example, whether the treatment is able to prevent relevant organ manifestations and reduce mortality due to Fabry disease. These and other questions are currently the subject of clinical research.

Conflict of interest statement
Dr Hoffmann and Professor Mayatepek have received unlimited, project bound, research support from Shire Germany GmbH, one of the manufacturers of recombinant human alpha-galactosidase A. Dr Hoffmann has also received honoraria for lectures from Shire Germany GmbH and Genzyme Ltd.

Manuscript received on 10 August 2008, revised version accepted on
18 December 2008.

Translated from the original German by Dr Birte Twisselmann.


Corresponding author
Dr. med. Björn Hoffmann
Klinik für Allgemeine Pädiatrie
Universitätsklinikum Düsseldorf
Heinrich-Heine-Universität
Moorenstr. 5
40225 Düsseldorf, Germany
hoffmann@med.uni-duesseldorf.de
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Klinik für Allgemeine Pädiatrie, Universitätsklinikum Düsseldorf, Heinrich-Heine-Universität: Dr. med. Hoffmann, Prof. Dr. med. Mayatepek
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