DIFFICULTIES IN DIAGNOSING FABRY DISEASE IN PATIENTS WITH UNEXPLAINED LEFT VENTRICULAR HYPERTROPHY (LVH): IS THE NOVEL GLA GENE MUTATION A PATHOGENIC MUTATION OR POLYMORPHISM?
Aladağ N, Ali Barman H, Şipal A, Akbulut T, Özdemir M, Ceylaner S
*Corresponding Author: Nesim Aladağ, MD, nesimaladag@hotmail.com, Van Yüzüncü yıl University, Faculty of Medicine, Department of Cardiology, Van, Turkey. Phone: +90 544 961 31 69 / Fax: +90 432 486 54 07
page: 43
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DISCUSSION
In this study, 120 patients with idiopathic LVH on
echocardiography were genetically screened for FD. A
genetic mutation was detected that was previously associated
with FD in one of the participants (Case 1). The
D313Y mutation was detected in another participant (Case
2). This mutation was previously described as a benign
GLA gene mutation. In the third participant (Case 3), a
result was obtained that is considered a polymorphism in
the foreground.
Variants in the α-GLA A gene present on the X chromosome
cause FD (1). Due to a deficiency in the α-Gal A
enzyme, the glycolipid Gb3 steadily accumulates within
lysosomes. The degree of X inactivation determines the
intensity of FD in females (4). Multisystemic involvement
is exhibited in FD (16). It is evident from the recurring
observation of cardiac involvement in FD that the heart is
extremely sensitive to α-GLA A (17, 18) and that cardiac
involvement is the main cause of morbidity and mortality
in patients with FD (10).
Differences in the incidence and occurrence of FD
signify variations in study design and population. There is
a low prevalence of the disease in the general population;
however, it is increasing in different at-risk patient populations,
for example, those with kidney failure, stroke, or
HCM (12). Nakao et al. determined seven patients to be
suffering from FD out of a group of 230 Japanese males
with LVH (12). Sachdev et al. identified six patients as
having FD out of 153 males with HCM (4%) in the United
Kingdom, with a prevalence of 6% for males diagnosed at
over 40 years of age (19). Ommen et al. determined that
out of 100 patients with HCM in the United States who
had undergone septal ablation, none had FD (20). Chimenti
et al. determined four Italian patients to have FD out of a
total of 34 females (12%) with HCM who had undergone
endomyocardial biopsy (17). Monserrat et al. screened
plasma for α-Gal A activity in a Spanish population of
patients with HCM and determined an FD prevalence of
almost 2% (0.9% in males and 1.1% in females). However,
this study included many variants of unknown significance
(21). Havndrup et al. identified three patients with FD from
a group of 90 patients with LVH in Denmark (18). Elliot
et al. identified seven patients with FD from a group of
1,386 European patients (3.4%) with HCM or unexplained
LVH (22). Hagege et al. performed systematic screening
for FD (an α-Gal A assay on dried blood spots via a filter
paper test) in a French population of patients diagnosed
with HCM and found four patients with FD from a total
of 278 males (23). However, Mawatari found no FD in a
Japanese population of 738 patients with unexplained LVH
(24). Five patients with FD were identified by Terryn et
al. from a group of 560 Belgian patients with unexplained
LVH (25). Out of a group of 100 Czech patients, Palecek
et al. found four patients with FD (26). Baptista et al.
performed screening for FD in Portuguese patients with
LVH, and a single case of FD was identified from a total
of 47 patients (27). A Spanish group of 805 patients with
clinical symptoms related to FD was examined by Vieitez
et al., and 21 patients were found to have FD (28). Maron
et al. performed screening for FD among patients from
North America with diagnosed HCM. The study found
two patients with FD from a total of 585 patients (29).
From a Korean group of 988 patients with LVH, Kim
et al. found five patients with FD (30). Similarly, in our
study, two patients out of 120 with unexplained LVH were
diagnosed with FD by genetic analysis (1.6%) (Figure 4).
In these screening studies, different LVH cut-off values
were used. Similarly, the diagnostic methods for FD varied
in these studies.
The D313Y genotype, previously described as a
benign mutation not clinically relevant to FD (15), was
reported in 2016 to have a significant impact on healthrelated
quality of life of respective individual patients.
This mutation might represent a confounding risk factor
for certain isolated symptoms, triggering a specific mild
clinical variant of FD (31).
During these screening studies, some of the genetic
mutations detected by genetic analyses were pathogenic,
while some were polymorphisms. For instance, Montserrat
et al. reported an incidence of 1% in the Spanish population
but includes many variants of unknown significance (21).
The difficulty lies in identifying GLA variants that may give
rise to the clinical symptoms of FD. There is a lack of en
zyme activity in patients with classic FD who have clinically
significant α-GLA A enzyme deficiency (32). It was found
that the residual activity of 30% to 35% of the mean normal
α-GLA A activity was the threshold for diagnosing FD (33).
There are three categories of α-GLA A residual activity
into which GLA variants are grouped. In the first
category, patients have benign GLA gene mutations and a
10% change in enzyme levels (34). In the second category,
enzyme activity is between 15% to 30% of the standard
activity in males (35). The clinical expression of the second
group is highly dependent on genetic and epigenetic modifiers.
In the third category, there is considerably reduced
enzyme activity (GLA variants less than 35% to 40% of
the average normal male controls). The true pathogenicity
threshold for FD in terms of enzyme levels is unknown.
Normal enzyme levels in male patients indicate benign
GLA variants and polymorphisms in these patients.
Since the enzyme levels of the patients in Case 2 and
Case 3 were normal, the genetic result was evaluated as
a predominantly benign GLA variant and polymorphism.
Their cardiomyopathy likely has another etiology, and the
variant found was a benign polymorphism. These results
demonstrate that enzyme activity levels alone are insufficient
to determine whether a particular GLA variant is
pathogenic. In addition to enzyme levels, the accumulation
of substrate in plasma or urine or altered sphingolipid
levels (Gb3 or lyso-Gb3) may be helpful in the diagnosis
of FD (14, 15). However, recognizing typical lysosomal
inclusions in tissue biopsy specimens is suggested as the
best method of diagnosing FD (36).
Fabry disorder is rare in that it is one of the metabolic
diseases that can be treated. As it is a progressive disease,
the early diagnosis of FD is vital, and it can be treated
with ERT and pharmacological chaperones (37). If FD is
diagnosed via screening, it is extremely important to screen
family members. Some individuals may be identified via
family screening who have not yet developed organ damage
(with the exception of the index case).
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