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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
J Am Coll Cardiol 2007;50:2399–403
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
Cardiac complication
Morbidity
Stroke
Renal failure
Decreased lifespan
Inheritance Pattern
Fabry Disease - Symptoms
• High Risk of Stroke, Hearing Loss & Vertigo
• High Risk of Heart Failure
• High Risk of Kidney Failure
• Can not Tolerate Temperature Variations
& Can not Sweat
• Stomach Pain & Digestive Problems
• Angiocharatomas
• Extreme Pain in Hands and Feet
Fabry Disease Progression
Cardiac Disease
CNS Disease
Renal Disease
Acroparesthesia
0
40+
[Age]
Clinical
Presentation
Diagnosis
(average)
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
plasma enzymatic activity measurement is cost-effective
not only in men but also in women with HCM
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)
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).