INTELLECTUAL ABILITY IN THE DUCHENNE
MUSCULAR DYSTROPHY AND DYSTROPHIN GENE
MUTATION LOCATION
Milic Rasic V1,2,*, Vojinovic D1, Pesovic J3, Mijalkovic G1, Lukic V1, Mladenovic J1,
Kosac A1, Novakovic I4, Maksimovic N4, Romac S3, Todorovic S1, Savic Pavicevic D3
*Corresponding Author: Vedrana Milic Rasic, M.D., Ph.D., Clinic for Neurology and Psychiatry for Children
and Youth, Dr. Subotica 6A, 11000 Belgrade, Serbia. Tel: +381-11-265-8355. Fax: +381-11-264-5064. E-mail:
vedrana.milic.npk@gmail.com
page: 25
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DISCUSSION
The aim of this study was to determine the frequency
of intellectual impairment and relationship
between intelligence level and dystrophin mutations
in the Serbian group of patients with DMD. Consistent
with previously published studies, general
intellectual level in our study group was statistically
significantly different from normative values [27].
The FSIQ was reduced for almost 1 SD (15 FSIQ
points) from population average, which is in agreement
with the results from other DMD cohorts [28-
30], or DMD plus intermediate MD cohorts [31].
Seven boys in our sample (18.92%) had intellectual
impairment with FSIQ<70, which is slightly lower
but still in agreement with the results reported in other
studies (19-35%) [2,3,28-30].
The majority of patients in our study had confirmed
causal deletion in the DMD gene, so it was
difficult to analyze the effect of mutation type on
intellectual level. Even though only four patients had
duplication in the DMD gene, three of them (IDs 3,
6 and 7) had normal intelligence ability, while for
one patient (ID 41), the estimated SQ, which highly
correlates with FSIQ, was low. The patients with
normal intellectual ability had a duplication in the
proximal part of the DMD gene that affected expression
of Dp427, while the patient with low SQ had
a duplication/triplication that altered the expression
of all dystrophin isoforms. Our study did not include
patients with DMD clinical presentation without deletion
or duplication and with possible point mutations.
However, Taylor et al. [14] published a study
in which there was no significant correlation between
mutation type and FSIQ. Despite the fact that some of the previously published
studies found association between the structural
location of mutations and FSIQ [22,23,28], we
were not able to replicate this association in our study
when boundaries for proximal and distal mutations
were set at exon 30 and exon 45. However, association
between the intellectual ability of DMD patients
and mutation location in regard to their functional
consequence, loss of expression of different dystrophin
isoforms [14], was confirmed with our results.
The loss of the Dp427 isoform is a common
feature among all DMD patients, which may result in
cognitive impairment. Dp427 is expressed in the neocortex,
cerebellum and amygdala [6,32,33], where it
plays not only a structural role in central synapses but
likely regulates GABAA receptor clustering at inhibitory
synapses [9]. In eight patients whose mutations
abolished the expression of Dp427, two boys (IDs
1 and 4) (25.0%) had borderline FSIQ, while none
had an intellectual impairment (FSIQ <70). However,
the mutations affecting the expression of Dp140 and
Dp71/Dp40, in addition to Dp427, have been associated
with higher frequency and severe cognitive impairment
in our DMD patients, suggesting the effect
of cumulative loss of dystrophin isoforms and the
important role of Dp140 and Dp71/Dp40 on intellectual
ability. This finding is in agreement with the
results of previously published studies [14,15,34-36].
The role of the Dp140 isoform on intellectual
functioning was recognized by Felisariet et al. [37],
who described the association between the mutations
affecting the expression of Dp140 and intellectual
ability in DMD patients, has been replicated in other
studies [14,28,29]. Dp140 is detected throughout the
brain (cerebral cortex, cerebellum, hippocampus,
brain stem and olfactory bulb) and in the spinal cord
[11], but its function is still unclear. Our results suggest
statistically significantly lower FSIQ in patients
with altered Dp140, Dp116, Dp71 and Dp40 compared
to patients with the mutations affecting only the
expression of Dp427 and Dp260. However, a statistically
significant difference has been obtained after
clustering mutations in the Dp140utr region together
with the mutations affecting the expression of Dp427
and Dp260. Additionally, statistically significant difference
in the mean FSIQ was obtained when patients
with the mutation affecting Dp140 were classified
into groups with the mutation localization in 5’UTR
(Dp140utr) or in promoter and protein-coding region
(Dp140pc). These results underline the importance of
assuming that the expression of the Dp140 isoform is
not mainly affected by mutations located in its long
5’UTR, which includes frequently deleted exons 45-
50. All the same, in our group of patients, three boys
(IDs 14, 19 and 21) with mutations in the Dp140utr
coding region were intellectually impaired, suggesting
that some regulatory elements in the 5’UTR might
be affected, influencing the alteration in the expression
of Dp140. Our results are in agreement with a
previously published study suggesting that mutations
in the Dp140utr have a lesser effect on FSIQ when
compared to the mutations affecting Dp140pc [14].
The Dp71 isoform is a major product of the
DMD gene in the brain. It has been confirmed that
Dp71 is abundant in the fetal as well as adult brain,
particularly in the cerebral cortex and hippocampus
[38]. Although the function of this isoform remains
unknown, it has been reported that Dp71 has a role
in the stabilization and/or formation of the synaptic
membrane [39]. The dysfunctions of proteins involved
in the regulation of synaptic structure and
function influence neuronal connectivity and the ability
of the brain to process information, and may be
related to the cognitive impairment [36]. Additionally,
it was shown that Dp71 has a regulatory role
in excitatory synapse organization and function, by
clustering glutamate receptors and organizing signaling
in postsynaptic densities [15]. The systematic
occurrence of mild-to-severe mental retardation was
noticed in more than 50 patients with dystrophinopathies
and the mutation located in the Dp71 [15].
Although the number of patients with altered Dp71 in
our study was small (n = 2), which is in accordance
with the low frequency of deletions and duplications
in the most distal part of the DMD gene, both patients
(IDs 36 and 37) were intellectually disabled,
whereas one (ID 36) had the lowest FSIQ (44) within
the entire study group. The mutations affecting the
expression of Dp71 also effect the expression of all
dystrophin isoforms, supporting the importance of
cumulative loss of dystrophin isoforms apart from the
loss of Dp71 only, reported in this and other studies
[14,15,34].
Until recently, the role of the shortest isoform
Dp40 in the brain was unknown. A finding that Dp40
is enriched in the synaptic vesicle fraction where it
assembles a group of presynaptic proteins involved
in the exocytosis of synaptic vesicles, indicates that Dp40 might have an important role in presynaptic
function [16]. Even though other studies did not analyze
the effect of Dp40, the patients with intellec-tual
impairment had mutations that influenced the expression
of both Dp71 and Dp40 [15,16,34], implying
that Dp40 might have a function relevant to cognitive
processes.
Interestingly, one pair of siblings who were observed
in our study, had the mutation that affects
Dp71, but the use of different psychological instruments
made it difficult to correlate genetic data with
cognitive ability assessment and to analyze variation
in DMD expression between siblings (IDs 37 and 40)
with the same mutations. Unlike the FSIQ, the DQ
is a ratio reflecting the child’s overall development
without precisely defined correlation with FSIQ in
later life. Still, the infant who scores low often turns
out to be intellectually disabled [40].
In addition, the association of DMD with neuropsychiatric
disorders has also been recognized. Wu
et al. [41] published a study in which they confirmed
a previously unrecognized relation between DMD
and an autistic spectrum disorder. Therefore, it is
not surprising that one boy (ID 38) with autism likebehavior,
qualitatively different from the behavior of
DMD boys with mental retardation, was described in
our sample. His SQ, which was estimated to be 41,
indicates below average achievement and impairment
in adaptability, including communication, daily
living, and socialization. The mutation in this boy
affected only the expression of Dp427.
The limitations of our study were the retrospective
design and limited sample size, but since psychological
testing is a standard procedure in the care
of DMD patients at the Clinic for Neurology and
Psychiatry for Children and Youth, Belgrade, Serbia,
we enabled an unbiased selection of recruited
patients, overcoming selection issues discussed in
other studies [2]. The non longitudinal design of our
study excluded the possibilities of defining subtypes
within DMD [23] and to define the clinical severity of
two very young DMD patients (IDs 2 and 38) with inframe
mutations. In general, in-frame mutations are
associated with milder form of dystrophinopathy, but
exceptions to the reading frame hypothesis exist [42].
In summary, the classification of the mutations
based on their functional consequence on dystrophin
isoforms, with the assumption that the expression
of Dp140 is not mainly affected by the mutations in
its 5’UTR, explained the genetic influence on variability
of FSIQ with the effect of cumulative loss of
dystrophin isoforms, suggesting an important role
of Dp140, Dp71 and Dp40 isoforms on intellectual
ability. Defining the functional loss of dystro-phin
isoforms allows the recognition of the subgroup of
DMD boys with greater risk for cognitive problems.
Early interventions and the support in cognitive, emotional
and behavioral development could be very
useful and more effective than interventions in the
older period of childhood or adolescence.
Declaration of Interest. This study was supported
by a grant from the Ministry of Education,
Science and Technological Development, Republic of
Serbia (project Nos. 17 3016 and 17 508). The authors
report no conflicts of interest. The authors alone are
responsible for the content and writing of this article.
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