Balkan Journal of Medical Genetics

ASSOCIATION BETWEEN LOSS OF Dp140 AND COGNITIVE IMPAIRMENT IN DUCHENNE AND BECKER DYSTROPHIES
Chamova T1,*, Guergueltcheva V1, Raycheva M1, Todorov T2,3, Genova J2, Bichev S4, Bojinova V5, Mitev V3, Tournev I1,6, Todorova A2,3
*Corresponding Author: Teodora Chamova, M.D., Ph.D., Clinic of Neurology, University Hospital “Alexandrovska”, 1 Georgi Sofiiski str., Sofia 1431, Bulgaria; Tel.: +359-889802252; Fax: +359-2-9526787; E-mail: teodoratch@abv.bg
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DISCUSSION

Dystrophinopathies provide a unique opportunity to investigate cognitive impairment caused by mutations in a single gene and to analyze the impact of a dysfunctional dystrophin in the complex pathogenesis of cognitive impairment. Among patients with dystrophinopathies, there is a higher rate of cognitive disorders and mental retardation than in the normally developing population [16,17]. In the present study, we found that the patients with DMD and IMD had typically lower average intelligence with a mean IQ of 86.98 ± 15.34, which is 1 SD below the population mean. The large SD reflects the enormous cognitive variation, found in the DMD patient group, whose IQs varied between 53 and 124. The results are consistent with previous studies [22,24]. Our BMD group had an IQ of 85.62 ± 10.40, which is close to some previous reports [18]. According to our data, there was not a statistically significant difference between the average IQ of patients with DMD, IMD and BMD on the one hand, but on the other hand, the percentage of mentally retarded DMD boys was greater (15.0 vs. 7.0%). The fact that in our study the number of DMD patients was larger than BMD patients shoud also be taken into consideration. In recent years, our knowledge concerning the function of dystrophin in CNS has expanded. The etiology of cognitive disturbances of patients with dystrophinopathies have been widely investigated [9-12,16,17,20,22,23]. Over the past few years, short distal dystrophin isoforms (Dp140, Dp71) with major cerebral expression have been discovered. Although Dp140 function is still unclear, we found a significant difference in cognitive performance in patients with a presumably intact dystrophin isoform Dp140 vs. patients in whom this isoform was predicted to be absent in the brain, due to mutations in the regulatory region or translation start-site. Our data showed a significant difference in general cognitive abilities between patients with an intact Dp140 isoform (90.31 ± 12.95) and patients whose deletion was predicted to be incompatible with the formation of an intact Dp140 (78.88 ± 13.98). Moreover, the Dp140[–] population was found to perform more poorly on tests measuring verbal memory, executive functions and attention compared to the Dp140[+] population. These data support the increasingly recognized role of Dp140 in the cognitive functioning of the brain. The problem with cognitive impairment seems to be more complex. Although two of our patients were brothers, sharing the same defect, deletion of exons 45-53 of the DMD gene and the same social background, their IQ differed by 18 points (83 and 65). Thus, we can suppose there are some modifying factors that should be thoroughly investigated. This is in contrast to the findings of Taylor et al. [20], who described good concordance in IQ not only among siblings but also among unrelated patients with the same mutations. In summary, the findings of the present study demonstrated that the cognitive profiles of patients with dystro-phinopathies is characterized by lower general intelligence compared to the healthy population. The frequency of mental retardation is higher in patients with DMD. Defective dystrophin isoforms (in particular Dp140) seem to be one of the major factors, influencing the neuropsychological development and functions in patients with DMD, IMD and BMD.

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