Fabry disease mimicking hypertrophic cardiomyopathy: genetic screening needed for establishing the diagnosis in women.
OBJECTIVE
Fabry disease, an X-linked storage disorder caused by defective lysosomal enzyme alpha-galactosidase A activity, may resemble sarcomere-gene-associated hypertrophic cardiomyopathy (HCM). The 'cardiac variant' of Fabry disease which only affects the heart may be missed unless specifically tested for.


RESULTS
We evaluated 90 consecutively recruited HCM probands and their relatives. Probands without sarcomere-gene mutations were tested for alpha-galactosidase A gene (GLA) mutations. Of the 90 families, 31 (34%) had sarcomere gene mutations and were therefore excluded. In the remaining 59 probands, 3 (5%) had GLA mutations as follows. The first proband, a female with asymmetric septal hypertrophy (ASH), a significant left ventricular outflow tract gradient, and chronic obstructive pulmonary disease, was heterozygous for a novel missense mutation (p.N139S). The second proband, a male with ASH and multiple episodes of ventricular tachycardia, was hemizygous for a missense mutation (p.A156T). His daughter was heterozygous, but had normal enzyme activity. The third proband was a female with ASH, and no other indices of Fabry disease. She was heterozygous for a GLA missense mutation (p.G271S). She had one affected daughter but her two other children were unaffected. The affected daughter had three children, of whom two were also affected--a boy aged 8 and a daughter aged 10 years.


CONCLUSIONS
This is the first report of systematic mutation screening of GLA in HCM patients without sarcomere gene mutations. GLA mutations were found in 3/90 (3%) of HCM families and in 2/20 (10%) of females without sarcomere-gene mutations. None of the probands presented other indices of Fabry disease. This, in combination with putative reversibility of cardiac changes by enzyme replacement therapy, supports systematic testing for Fabry disease. Enzyme measurements are sufficient in men, but genetic testing is needed in women.
Havndrup
Ole
O
Department of Cardiology, Heart Centre, The National University Hospital, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark.
Christiansen
Michael
M
Stoevring
Birgitte
B
Jensen
Morten
M
Hoffman-Bang
Jakob
J
Andersen
Paal Skytt
PS
Hasholt
Lis
L
Nørremølle
Anne
A
Feldt-Rasmussen
Ulla
U
Køber
Lars
L
Bundgaard
Henning
H
D000293:Adolescent; D000328:Adult; D000368:Aged; D002312:Cardiomyopathy, Hypertrophic / Q000175:diagnosis*; D002648:Child; D002675:Child, Preschool; D003937:Diagnosis, Differential; D000795:Fabry Disease / Q000175:diagnosis* / Q000235:genetics; D005260:Female; D005820:Genetic Testing; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D055815:Young Adult; D000519:alpha-Galactosidase / Q000235:genetics*
D000519:alpha-Galactosidase