Review
When Should Cardiologists Suspect Anderson-Fabry Disease?

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Anderson-Fabry disease is a lysosomal storage disorder caused by α-galactosidase defects and progressive intracellular accumulation of globotriaosylceramide. The disease can be specifically treated with enzyme replacement therapy. Hemizygous men and heterozygous women can develop cardiac disease. Whereas men experience the most severe clinical phenotype, clinical presentation in women varies from asymptomatic to severely symptomatic. The characteristic cardiac phenotype is left ventricular hypertrophy mimicking sarcomeric hypertrophic cardiomyopathy or hypertensive heart disease. Early or prehypertrophy cardiac involvement may escape detection, unless electrocardiographic clues are present. The cardiac markers that raise suspicion of Anderson-Fabry disease include a short PR interval without a δ wave and a prolonged QRS interval, supraventricular and ventricular arrhythmias, and concentric left ventricular hypertrophy. Extracardiac features include renal failure, corneal deposits, and nervous, gastrointestinal, and cutaneous manifestations. Useful family data include cardiac and extracardiac traits in relatives and absence of male-to-male transmission. Symptoms are subtle, and the interval between the onset of symptoms and diagnosis may be as long as 20 years. As such, the diagnosis is typically late. Endomyocardial biopsy shows optically empty myocytes on light microscopy and dense osmiophilic bodies constituted of globotriaosylceramide on electron microscopy. Alpha-galactosidase A activity is reduced in hemizygous men but not in heterozygous women. Genetic testing is the gold standard for the diagnosis. In conclusion, a correct and timely diagnosis offers the possibility of disease-specific treatment that leads to sustained clinical benefits for cardiac and noncardiac signs and symptoms.

Section snippets

Clinical Scenarios

In each of the following scenarios, the family history and clinical traits in probands and relatives are highly informative for suspecting AFD. A disease-oriented interview is the first low-cost step of the diagnostic workup.

Electrocardiography

Incidental findings of a short PR interval without a d wave (below the lower limit for age in children15, 16 and <120 ms in adults17) in subjects who undergo electrocardiography for cardiac or noncardiac reasons (presurgery evaluation, sport suitability, etc.) should be considered with caution as early potential markers of a myocardial storage disease18 (Figure 2). A short PR interval is seen in 21% to 40% of adult patients with AFD17, 19, 20, 21 and in about 28% of pediatric patients.14 The PR

Differential Diagnosis Between Anderson-Fabry Disease and Sarcomeric Cardiomyopathy

A disease-oriented process of differential diagnosis between sarcomeric and nonsarcomeric HC, including AFD, can be supported by type of inheritance, instrumental markers, and clinical data that may guide biochemical and genetic testing. Table 2 lists the major cardiac and noncardiac traits that may help differential diagnoses.

Genetic Testing and Counseling

Genetic counseling should be performed before genetic testing, according to international guidelines and recommendations for adults and minors.48, 49

In hemizygous men, the fastest and cheapest way to perform the test is by direct automated sequencing of the coding and flanking regions of the gene. The dosage of α-galactosidase activity is usually highly informative. In heterozygous women, assays for detecting heterozygosity followed by automated sequencing of heteroduplex amplicons is the

Treatment of Anderson-Fabry Disease

Since 2001, the availability of ERT has mandated that a correct diagnosis of AFD be made. Two drugs are available: agalsidase alfa and agalsidase beta. The former has had marketing authorization in Europe since 2001 and is undergoing Biologics License Application filing in the United States. The latter has been marketed in the United States and in Europe since 2001. Patients with proved diagnosis of AFD should be informed about ERT, its method and frequency of administration, contraindications,

Conclusions

Cardiologists may play a key role in suspecting and diagnosing AFD. In a disease-oriented mind-set, simple and low-cost tools such as family medical history, electrocardiography, and echocardiography may raise the diagnostic hypothesis. Endomyocardial biopsy is highly contributory, and genetic testing is the gold standard for diagnosis. Although the final decision for treatment is up to patients, the availability of ERT makes the diagnosis mandatory.

Acknowledgment

We are grateful to patients and families for their support in the activities of our center and for their helpful contributions in the critical discussion about their disease during counseling. We are also grateful to Monica Concardi and Anna Liew for their professional support of this study.

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    This study was supported by “Ricerca Corrente GIMAF: Gruppo di Studio Interdisciplinare per la Sindrome di Anderson Fabry” from the National Ministry of Health, Rome, Italy, to IRCCS Policlinico San Matteo and by Fondazione Cariplo, Milan, Italy.

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