J Am Coll Cardiol 2007;50:2399–403 Prevalence of Fabry Disease in a Cohort of 508 Unrelated Patients With Hypertrophic Cardiomyopathy Lorenzo Monserrat, Juan Ramon Gimeno-Blanes, Francisco Marin, Manuel Hermida-Prieto, Antonio Garcia-Honrubia, In maculada Pérez, Xusto Fernandez, Rosario de Nicolas, Gon zalo de la Morena, Eduardo Paya, Jordi Yagüe, Jesús Egido A Coruña, Murcia, Alicante, Barcelona, and Madrid, Spain

Introduction Fabry Disease X-linked inborn error of metabolism Deficient  -Galactosidase A (  -GAL A) enzyme activity Progressive globotriaosylceramide (GL-3) accumulation multiple cell types and tissues -- end organ impairment Progressive Multiple organ systems Morbidity Cardiac complication Stroke Renal failure Decreased lifespan

Inheritance Pattern

Fabry Disease - Symptoms Extreme Pain in Hands and Feet Angiocharatomas Stomach Pain & Digestive Problems High Risk of Heart Failure High Risk of Stroke, Hearing Loss & Vertigo Can not Tolerate Temperature Variations & Can not Sweat High Risk of Kidney Failure

0 Acroparesthesia Renal Disease CNS Disease Cardiac Disease [Age] 40+ Diagnosis (average) Clinical Presentation Fabry Disease Progression

Diagnosis of Fabry Disease Presumptive diagnosis observation of symptoms and laboratory findings family history/medical pedigree Definitive diagnosis enzyme assay in plasma, leukocytes, tears, or biopsied tissue Markedly deficient in affected males (very low to no enzyme activity) Carrier females can have low to normal levels Therefore it can be used to screen the males in a family but not the females gene mutation analysis or linkage analysis determine specific genetic mutation within family useful for precise carrier ID and prenatal diagnosis (therefore is diagnostic testing for women)

Introduction Hypertrophic cardiomyopathy more than 400 different mutations in genes encoding sarcomeric proteins 30% to 40% of the patients – cannot find these mutations Fabry disease as a relatively frequent cause of idiopathic left ventricular hypertrophy Prevalence of Fabry disease in a wide nonselected population of patients previously diagnosed with HCM

Materials and Methods Study protocol and patient enrollment 508 consecutive unrelated patients with HCM 3 regional centers (Coruña, in northern Spain; Murcia and Alicante, in southern Spain) all of the first-degree relatives were invited to be screened DNA from lymphocytes  -galactosidase A : assayed fluorometry -> activity GLA gene

Results

Table 1 Clinical Characteristics and Sudden Death Risk Factors of the Index Patients

Table 2 Summary of the Enzymatic and Genetic Screening of the Index Patients

Table 3 Genotype and Phenotype in the Index Patients With Low Enzymatic Activity

Figure 1 Pedigrees of the Families With Fabry Disease

Discussion 1% prevalence of FD in unselected patients with HCM Nakao et al. : 7 pts in 230 men with LVH (3%) Sachdev et al. : 6 pts in 153 men with HCM (4%) Ommen et al. : no FD Chimenti et al. : 4 pt in 34 women with HCM by endometrial Bx prevalence of HCM in the adult general population : 1 in 500 prevalence of FD in HCM : 1 in 100 prevalence of FD in the adult general population : 1 in 50,000

Discussion Screening :  -galactosidase A enzymatic activity Male : very low enzymatic activity Female carriers : within the normal range 7 women with a borderline activity (30% to 50% of the control) Several polymorphisms but no pathogenic mutation Classical (L89P, E358del) : early manifestation of the multisystemic disorder Late-onset (A143T) : in men with some residual plasma enzymatic activity or in female carriers S238N : incomplete penetrance in young carriers (even in men) plasma enzymatic activity measurement is cost-effective not only in men but also in women with HCM

Conclusion With a screening based on genotyping of patients with low plasma enzymatic activity, the prevalence of FD in our population with HCM was 1% (0.9% in men and 1.1% in women).