Milic Rasic V, Vojinovic D, Pesovic J, Mijalkovic G, Lukic V, Mladenovic J, Kosac A, Novakovic I, Maksimovic N, Romac S, Todorovic S, Savic Pavicevic D
Clinic for Neurology and Psychiatry for Children and Youth, Belgrade, Serbia ; Faculty of Medicine, University of Belgrade, Belgrade, Serbia.
Clinic for Neurology and Psychiatry for Children and Youth, Belgrade, Serbia.
Balkan J Med Genet. 2015 Apr 10;17(2):25-35. doi: 10.2478/bjmg-2014-0071. eCollection 2014 Dec.
Duchenne muscular dystrophy (DMD) is the most common form of muscular dystrophy during childhood. Mutations in dystrophin (DMD) gene are also recognized as a cause of cognitive impairment. We aimed to determine the association between intelligence level and mutation location in DMD genes in Serbian patients with DMD. Forty-one male patients with DMD, aged 3 to 16 years, were recruited at the Clinic for Neurology and Psychiatry for Children and Youth in Belgrade, Serbia. All patients had defined DMD gene deletions or duplications [multiplex ligation-dependent probe amplification (MLPA), polymerase chain reaction (PCR)] and cognitive status assessment (Wechsler Intelligence Scale for Children, Brunet-Lezine scale, Vineland-Doll scale). In 37 patients with an estimated full scale intelligence quotient (FSIQ), six (16.22%) had borderline intelligence (70<FSIQ ≤85), while seven (18.92%) were intellectually impaired (FSIQ <70). The FSIQ was not associated with proximal and distal mutations when boundaries were set at exons 30 and 45. However, FSIQ was statistically significantly associated with mutation location when we assumed their functional consequence on dystrophin isoforms and when mutations in the 5'-untranslated region (5'UTR) of Dp140 (exons 45-50) were assigned to affect only Dp427 and Dp260. Mutations affecting Dp140 and Dp71/Dp40 have been associated with more frequent and more severe cognitive impairment. Finally, the same classification of mutations explained the greater proportion of FSIQ variability associated with cumulative loss of dystrophin isoforms. In conclusion, cumulative loss of dystrophin isoforms increases the risk of intellectual impairment in DMD and characterizing the genotype can define necessity of early cognitive interventions in DMD patients.
杜氏肌营养不良症（DMD）是儿童期最常见的肌营养不良症形式。抗肌萎缩蛋白（DMD）基因突变也被认为是认知障碍的一个原因。我们旨在确定塞尔维亚DMD患者的智力水平与DMD基因中突变位置之间的关联。在塞尔维亚贝尔格莱德的儿童和青少年神经科与精神科诊所招募了41名年龄在3至16岁之间的男性DMD患者。所有患者均进行了明确的DMD基因缺失或重复检测[多重连接依赖探针扩增（MLPA）、聚合酶链反应（PCR）]以及认知状态评估（韦氏儿童智力量表、布鲁内 - 勒津量表、文兰 - 多尔量表）。在37名估计有全量表智商（FSIQ）的患者中，6名（16.22%）有边缘智力（70＜FSIQ≤85），而7名（18.92%）存在智力障碍（FSIQ＜70）。当以第30和45外显子为界限时，FSIQ与近端和远端突变无关。然而，当我们假设它们对抗肌萎缩蛋白异构体的功能影响，并且将Dp140（第45 - 50外显子）的5'非翻译区（5'UTR）中的突变仅归为影响Dp427和Dp260时，FSIQ与突变位置在统计学上有显著关联。影响Dp140和Dp71/Dp40的突变与更频繁、更严重的认知障碍有关。最后，相同的突变分类解释了与抗肌萎缩蛋白异构体累积缺失相关的FSIQ变异性中更大的比例。总之，抗肌萎缩蛋白异构体的累积缺失增加了DMD患者智力障碍的风险，并且对基因型进行特征分析可以确定DMD患者早期认知干预的必要性。
