SYMPTOMS AND CLINICAL COURSE

The presenting symptoms of affected individuals and the clinical course of Fabry disease are highly variable. Acroparesthesia, with an onset in early childhood, constitutes one of the earliest and most debilitating symptoms and is often accompanied by fever, hypohidrosis, and heat intolerance. Other characteristic features are lenticular and corneal opacities, angiokeratoma, edema, and abdominal pain. During the third and fourth decade of life, Fabry disease is characterized by a progressive course and severe morbidity due to cardiac, renal, and cerebrovascular involvement⁴. Renal disease is one of the major causes of morbidity and mortality in Fabry patients⁵. In classically affected males, the first renal manifestations can be observed as proteinuria, microhematuria, and lipiduria. With advancing age, most of these patients show progressive renal failure. ESRD typically occurs in the third to fifth decade of life⁵. Myocardial involvement in patients with Fabry disease is well documented with concentric or asymmetrical left ventricular hypertrophy (LVH)^6,7. Clinical signs of cardiac involvement typically occur late in the course of the disease and many patients die from heart failure^8,9. Further complications include conduction abnormalities with reduced PR-interval¹⁰ and cardiac arrhythmias¹¹. Typical cerebrovascular symptoms in classic male patients are vertigo, headache, diplopia, dysarthria, and hemiataxia. There is an elevated risk for transient ischemic attacks, premature stroke, and dementia^12,13.

DIAGNOSIS

Classic features of Fabry disease are painful attacks of burning pain predominantly in the upper and lower extremities, which occur in 80% to 90% of patients. In combination with hypohidrosis, heat intolerance, and characteristic angiokeratomas, these patients are highly susceptible for classic Fabry disease. Pathognomonic symptoms are corneal opacities (cornea verticillata) and typical conjunctival involvement. The presumptive diagnosis based on the symptoms above is supported by a positive family history. The clinical diagnosis must be confirmed by assay of -GAL A activity in leukocytes or plasma, and/or detection of GL3 deposition in tissue biopsies, and should be followed by a molecular genetic analysis. Taking pedigrees of newly diagnosed patients is worthwhile and may reveal more affected individuals.

ESTABLISHING A DIAGNOSTIC AND TREATMENT CENTER FOR FABRY DISEASE

In March 2001, our institution launched an outpatient center for the diagnosis and treatment of Fabry disease. The objectives of the center are to raise awareness of Fabry disease, to identify patients with no previous diagnosis, and to make ERT accessible to all Fabry patients with an indication for treatment. We seek to enroll sufficient numbers of patients in this evaluation program to reveal efficacy and safety of ERT in clinical practice. Subsequently, all patient data are anonymously entered into the Internet-based international Fabry registry. The majority of patients who have attended our center were referred by adult nephrologists or internists. All patients are provided with a confirmed diagnosis through determination of -GAL A activity and/or genotyping. Indication for therapy is established and this may depend on age, sex, and severity of symptoms. Affected males are all considered to have an indication for therapy, but females and children undergo further evaluation to determine their suitability for treatment.

PATIENT EVALUATION PROGRAM

Due to the variety and variability of possible manifestations, every patient with confirmed diagnosis of Fabry disease undergoes a comprehensive clinical evaluation program before treatment is started Table 1. This baseline set of data serves to determine advanced organ damage and allows the benefits of ERT to be quantitated during follow-up. To date, all patients who have undergone the initial evaluation have agreed to participate. Parts of the program have been approved by the local ethical committee and patients have given written consent according to the principles of the declaration of Helsinki.

Table 1 - Evaluation tests conducted on all patients recruited to the Würzburg outpatient center before start of enzyme replacement therapy for Fabry disease.

Full table

Echocardiography

To detect cardiac involvement at an early stage of the disease, sensitive noninvasive imaging techniques are of clinical benefit. In addition to conventional echocardiography, we have introduced ultrasound-based strain rate imaging in the surveillance of regional LV function before and during ERT. This new technique has been shown to quantify regional changes in myocardial deformation properties¹⁴. Myocardial strain measurements have been validated both in correlative experimental sonomicrometry¹⁵ and in clinical studies¹⁶.

Magnetic resonance imaging (MRI) and spectroscopy (MRS)

MRI allows quantitative assessment of cardiac morphology and function with high accuracy and objectivity, as well as detection of inflammatory alterations in the myocardium, using contrast enhancement techniques^17,18. MRS offers the additional possibility to detect fundamental metabolic derangements in cardiomyocytes, which allow detection of subclinical cardiac commitment in different kinds of heart disease¹⁹. For MRS, absolute concentrations of energy metabolites, such as adenosine triphosphate (ATP) and phosphocreatine (PCr), are measured and an energetic index can be determined²⁰.

Kidney function and biopsy

Kidney function in patients enrolled so far in clinical trials has been well preserved^21,22. However, pretreatment biopsies revealed that these patients had extensive renal deposition of GL3 at study entry. This experience suggests that serum creatinine may not be an adequate parameter to investigate the benefit of ERT in moderate to severe renal disease. Renal function is estimated by measurement of the glomerular filtration rate (GFR), as well as by 24-hour creatinine clearance, or even more accurately by techniques using nuclear trace material (^99mTc-DTPA). Additional information can be obtained by measuring 24-hour albuminuria/proteinuria. Kidney biopsy should be performed whenever patients are enrolled in a controlled clinical program. In the absence of significant urinary protein excretion, and when the extent of kidney damage is difficult to determine, the performance of a renal biopsy may provide helpful information.

Figure 1.

Typical angiokeratomas in Fabry disease. Characteristic dark-red to blue-dark angiectases, typically found between the umbilicus and thigh. The lesions range in size from pinpoint to several millimeters.

Full figure and legend (119K)

TREATMENT OPTIONS

At present, treatment of Fabry disease is limited to symptom management. ACE inhibitors and antihypertensive drugs may delay progressive loss of renal function. Therapy of heart disease includes antiarrhythmic drugs, artificial pacemakers, and coronary bypass grafting in case of coronary heart disease. For patients with chronic pain, the use of gabapentin, carbamazepin, or phenytoin is recommended. New therapeutic approaches for causal or specific treatment of Fabry disease, such as substrate deprivation or gene therapy, are promising but will not be available in the near future^23,24.

Figure 2.

Electron micrograph showing the electron dense lipid depositions in the vascular endothelium (arrows) of a skin capillary from a 29-year-old male Fabry patient (magnification x 3000).

Full figure and legend (115K)

A new specific treatment option that has reached the stage of clinical use is ERT. After cloning the -GAL gene²⁵ and making advances in molecular genetic techniques, recombinant -GAL is now synthesized by genetically engineered cell lines and available in two enzyme formulations. Safety and efficacy of the two enzyme preparations have been tested in preclinical studies^26,27. Subsequently, the enzymes were evaluated in two randomized, double blind, and placebo-controlled trials with 26 patients (agalsidase alpha) and 52 patients (agalsidase beta), respectively. Agalsidase alpha was given intravenously every 14 days at a dose of 0.2 mg/kg/body weight for 24 weeks²¹, and a significant reduction of neuropathic pain (primary end point) was demonstrated. Initial kidney function was well preserved and remained stable in the treatment group, whereas a deterioration of GFR was found in the placebo group. The second study used agalsidase beta at a dose of 1 mg/kg/body weight²². Primary end point was the clearance of interstitial microvascular GL3 deposits in renal biopsy specimens. After 20 weeks of ERT, there was a significant reduction of depositions in the treatment compared with the placebo group. This was also noted in heart and skin specimens. Initial renal function (GFR and serum creatinine) was normal and remained stable throughout the study in both groups.

PERSPECTIVES

The response to ERT, obtained during the treatment period of one year, demonstrates a powerful clearance of microvascular lipid depositions, and a clear potential to improve the clinical symptoms of the disease. Treatment outcome in the long run concerning severe organ manifestations, such as proteinuria, renal function impairment, LVH, and heart failure remains to be shown. Observation over longer treatment periods are needed to assess the value of ERT in patients with advanced organ damage if a definite improvement, or at least stabilization, can be demonstrated. Thus, in a rare disorder like Fabry disease, it is important to collect sufficient and comparable baseline and long-term clinical data on patients under treatment in specialized centers. ERT should be initiated by these centers to obtain a baseline data set and a thorough documentation of the clinical course. At present, it appears that an early intervention, without waiting for organ manifestations such as proteinuria or LVH, should be the goal. A study among 20 heterozygote females showed that severe manifestations, such as reduced GFR, lymphedema, and cardiomyopathy, were present in more than 50% of the patients; symptoms like acroparesthesia and vertigo were seen in 90% of the patients²⁸. Similar results were reported in a British survey among female carriers²⁹, indicating the need for evaluation and therapy not only for affected males but also for symptomatic women. Screening studies among high-risk populations, such as patients suffering from unexplained myocardial hypertrophy or ESRD, have revealed a surprisingly high prevalence of unrecognized Fabry disease as the underlying cause^30,31. There are similar reports about renal variants that develop renal failure and about the significant prevalence of undiagnosed Fabry patients among patients on hemodialysis. Interestingly, these cardiac and renal variants seem to have residual enzyme activity and do not develop classical symptoms^9,32.

References

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