Clinical Interpretations
As part of the IMPRESsion study, we included a list of clinical features
associated with the different types of MPS, which clinicians were asked
to fill out. The heatmap of the clinical features associated with each
MPS type is depicted in Figure 2. In general, the trends and patterns
observed in the heatmap are in line with previous findings. As with
other literature reports, our analysis revealed that MPS I, MPS II, and
MPS VI share a wide range of symptoms, and the heatmap indicates that
symptoms are more concentrated in the same areas for these three types.
However, there were no reports of corneal opacity, visual impairment,
and cardiac valve defect among MPS II patients participating in our
study, while these clinical features have been reported in previous
studies (Martin et al. 2008; Montano et al. 2016; Muenzer et al. 2009,
2011). High occurrence of developmental and neurological problems among
our MPS III patients was also suggested by the literature, as well as
the rarity of skeletal abnormalities (M. J. Valstar et al. 2010).
Moreover, the symptoms of MPS IV patients in our study fell in line with
the known symptoms of this disease, with a high frequency of skeletal
abnormalities and no cognitive impairment reported in our patients
(Northover, Cowie, and Wraith 1996; Tomatsu et al. 2011).
Treatment of MPS is highly contingent
on the type of the disease, which can be conclusively determined by
molecular studies. While NGS provides a way to analyze all MPS genes
with high specificity, it is an expensive technique, which requires
well-equipped labs with high standards and specialized technicians. On
the other hand, Sanger sequencing is a less complicated and more
commonly available technique. By cross-referencing geographical patterns
of frequent variants, it is possible to develop a stepwise diagnostic
approach that can be used on clinically diagnosed MPS patients before
they undergo costly biochemical assays or NGS analysis. This method can
be helpful since we were able to identify variants that account for a
significant proportion of the MPS patients originating from specific
geographical regions as well as a few possible founder mutations. To
illustrate, the c.430G>A in ARSB is concentrated in
the southeastern regions of Iran, accounting for 88.2% of MPS VI
patients, while c.962C>T is responsible for 85.7% of MPS
VI cases in northwestern regions. Such patterns justify checking for
c.430G>A and c.962C>T in MPS VI patients
originating respectively from southeast or northwest before going
through further diagnostic approaches, which could lead to a conclusive
result at a fraction of the cost and effort. The same approach is
suggested for MPS IV patients originating from East Azerbaijan, where
c.319G>A in GALNS is responsible for 50% of MPS IV
patients. Therefore, a stepwise genetic testing starting from
c.319G>A analysis can be considered before performing a
more comprehensive analysis.