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
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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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