Event-Related Potentials (P300 - MMN) and Neuropsychological Assessment in Duchenne Muscular Dystrophy Patients

Over the last decade, several studies have been published concerning cognitive impairment in neuromuscular disorders. DMD is caused, in most cases, by large out-of-frame deletions or duplications in the dystrophin gene [21]. The dystrophin gene is the largest gene that is expressed predominantly in skeletal and cardiac muscle with small amounts in the brain [22,23]. Three isoforms that have the same number of exons, but which are derived from three independent promoters in brain, muscle, and Purkinje cerebellar neurons, were recognized. The brain promoter drives expression primarily in cortical neurons and the hippocampus of the brain [24]. Different brain localizations of dystrophin isoforms may explain the role of the protein in cognitive development [7]. In particular, the severity and frequency of mental retardation increases with the successive loss of functional distal isoforms. Bardoni et al., [9], and Moizard et al., [10], found a statistically significant correlation between the absence of Dp140 and Dp71 promoters, respectively, and the presence of mental retardation in patients.

In a meta-analysis of patients reported by Emery and Muntoni, of 721 children studied in 14 reports, the mean IQ was 82, 202 children had an IQ below 70, and 32 had an IQ below 50 [25]. In the present study, the mean full-scale IQ was 72. In addition to the commonly reported delays in motor milestones, another study documented delays in the acquisition of language milestones as well [26]. Several studies compared performance with verbal IQs and most concluded that verbal IQ was more affected; the difference from performance IQ was approximately 5-8 points [27]. In the current study, the researchers found that mean verbal IQ was 71 and mean performance IQ was 75.7. Consequently, the difference was 4.7 points.

Event related potentials are related to the basic aspects of brain mechanisms. P300 represents the outcome of attention dependent systems and information processing. They have been used for a long time for the assessment of cognitive functions. The auditory P300 response has been studied in mentally retarded patients diagnosed with Fragile X syndrome, Down's syndrome, and Alzheimer's disease in Down's syndrome [28,29]. In all these studies, mentally retarded subjects were found, regardless of the etiology of their retardation, to have increased in latency and reduced in amplitude of the P300 response. In the literature, there is only one study that evaluated P300 in DMD patients. Della Coletta et al., [18] found poor performance in DMD patients as evaluated by P300 potential compared to the control group, although the difference was not statistically significant. In the present study, the researchers found no statistical difference in mean P300 values between the groups. The brain promoter of the dystrophin gene drives expression primarily in cortical neurons and the hippocampus of the brain [24]. On the other hand, P300 shows electrical activity in the entire brain. Consequently, it is possible to explain why the difference is not significant. Besides, the power for many variables is under eighty percent so it may be due to lack of power and small sample size.

MMN response reflects pre-attentive auditory information processing. Some studies evaluated the MMN test in children with autism, and attention deficit hyperactivity disorder in the literature [30,31]. The magnitudes of MMN were significantly lower than the controls. Holopainen et al., [32] showed that in both the mentally retarded and dysphasic groups, the peak amplitude of the frequency MMN was significantly attenuated when compared with the control group, but no significant difference was observed between the mentally retarded and dysphasic groups. In the current study, magnitudes of MMN were similar in the patient and control groups, which reflects no central auditory defects and information processing in this patient group.

To date, neurocognitive functions were not evaluated with MMN and correlations of ERPs through neuropsychological tests were rarely investigated in children with DMD. MMN and P300 are easy, safe, and inexpensive endogenous potentials that may reflect cognitive functions in such patients. Although the patients had low IQ, the researchers did not find any statistical difference in P300 and peak MMN values. The small number of patients may explain these results. However, the peak latencies of MMN were longer in DMD patients. It may be appropriate to do large-scale studies in DMD patient groups with specific genetic defects that cause to mental retardation.

We thank Bulent Ozkan, Ph.D., from Biostatistics & Medical Informatics Department, School of Medicine Izmir Katip Celebi University, for the statistical analysis.