Genotype and phenotype characterization in a large dystrophinopathic cohort with extended follow-up
Genotype and phenotype characterization in a large dystrophinopathic cohort with extended follow-up
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DOI：
10.1007/s00415-011-5979-z
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发表时间：
2011-09-01
影响因子：
6
通讯作者：
Comi, Giacomo Pietro
中科院分区：
文献类型：
--
作者：
Magri, Francesca;Govoni, Alessandra;Comi, Giacomo Pietro
杜氏肌营养不良症和贝克尔肌营养不良症（分别为 DMD 和 BMD）是等位基因疾病，具有不同的临床表现和严重程度，由编码肌膜肌营养不良蛋白的 DMD 基因突变决定。诊断基于临床方面和肌肉蛋白分析，然后进行分子确认。我们修改了肌营养不良病自然史的主要方面，以在长期随访的大型患者队列中定义基因型-表型相关性。我们还专门探索了 DMD 基因中携带核苷酸取代的受试者，这是一个相对较少研究的 DMD/BMD 亚组。我们研究了 320 名肌营养不良症患者（205 名 DMD 和 115 名 BMD），定义了肌肉、心脏、呼吸和认知受累情况。我们还根据分子缺陷的类型（缺失、重复、核苷酸取代或其他微重排）和突变位点（外显子 45 的近端/远端）对患者进行细分，研究每组的表型-基因型相关性。在 DMD 中，突变类型不影响临床演变；位于远端区域的突变（无论其性质如何）更有可能与较低的智商水平相关（p = 0.005）。带有近端缺失的 BMD 显示出比带有远端缺失的 BMD 更高程度的心脏损害 (p = 0.0046)。在 BMD 人群中，肌营养不良蛋白缺乏的实体与临床病程之间存在很强的相关性 (p = 0.002)。对自然史的准确了解可能有助于患者的临床管理。此外，一些临床试验正在进行或正在计划中，其中一些旨在针对特定的 DMD 突变：因此，强大的自然史对于正确设计这些实验试验至关重要。
Duchenne and Becker muscular dystrophy (DMD and BMD, respectively) are allelic disorders with different clinical presentations and severity determined by mutations in the gene DMD, which encodes the sarcolemmal protein dystrophin. Diagnosis is based on clinical aspects and muscle protein analysis, followed by molecular confirmation. We revised the main aspects of the natural history of dystrophinopathies to define genotype-phenotype correlations in large patient cohorts with extended follow-up. We also specifically explored subjects carrying nucleotide substitutions in the DMD gene, a comparatively less investigated DMD/BMD subgroup. We studied 320 dystrophinopathic patients (205 DMD and 115 BMD), defining muscular, cardiac, respiratory, and cognitive involvement. We also subdivided patients according to the kind of molecular defect (deletions, duplications, nucleotide substitutions or other microrearrangements) and the mutation sites (proximal/distal to exon 45), studying phenotype-genotype correlations for each group. In DMD, mutation type did not influence clinical evolution; mutations located in distal regions (irrespective of their nature) are more likely to be associated with lower IQ levels (p = 0.005). BMD carrying proximal deletions showed a higher degree of cardiac impairment than BMD with distal deletions (p = 0.0046). In the BMD population, there was a strong correlation between the entity of muscle dystrophin deficiency and clinical course (p = 0.002). An accurate knowledge of natural history may help in the clinical management of patients. Furthermore, several clinical trials are ongoing or are currently planned, some of which aim to target specific DMD mutations: a robust natural history is therefore essential to correctly design these experimental trials.