Salort-Campana E, Nguyen K, Lévy N, Pouget J, Attarian S
Centre de référence des maladies neuromusculaires et de la SLA, hôpital La-Timone, avenue Jean-Moulin, 13005 Marseille, France; Inserm UMR_S 910 de génétique médicale et de génomique fonctionnelle, faculté de médecine secteur Timone, université Aix-Marseille, 27, boulevard Jean-Moulin, 13385 Marseille cedex 5, France.
Rev Neurol (Paris). 2013 Aug-Sep;169(8-9):573-82. doi: 10.1016/j.neurol.2013.07.001. Epub 2013 Sep 4.
Diagnosis of facioscapulohumeral dystrophy type 1 (FSHD1) is supported by a suggestive clinical presentation and associated with a heterozygous contraction of the D4Z4 repeat array on chromosome 4q35.
The FSHD1 phenotype has a widely variable course with great inter- and intrafamilial heterogeneity. Three clinical forms can be distinguished: the classical phenotype associated with four to seven repeat units (RU) and a variable course, a severe infantile form with one to three RU, and a mild phenotype associated with borderline UR (8 to 10 RU). At the molecular level, for D4Z4 contraction to be pathogenic, it needs to occur on a specific chromosomal background, namely on the 4qA allelic variant of chromosome 4. In most cases, once FSHD is clinically suspected, the diagnosis can be genetically confirmed with a DNA test using Southern Blotting and hybridization to a set of probes. However, diagnosis of FSHD1 remains challenging. Firstly, some patients may present with an atypical phenotype with highly focal or unusual symptoms. Secondly, there are potential pitfalls in the genetic diagnosis of FSHD resulting in false positive or false negative results. In the absence of genetic confirmation, other investigations, mainly EMG and muscle biopsy, are needed to rule out another diagnosis. In cases with no clear diagnosis and a permissive chromosome without contraction, FSHD2 may be suspected.
Molecular combing is a new technique which permits visualization and sizing of the D4Z4 repeat array on its genetic background on stretched single DNA fibers by fluorescence microscopy. This tool will improve genetic diagnosis in FSHD patients.
Diagnosis of FSHD1 is mainly supported by clinical features. Clinicians need to be aware of unusual presentations of this disease. The wide spectrum of intrafamilial variability and the lack of good correlation between genotype and phenotype present challenges for genetic counseling and prognostication. More studies are needed concerning penetrance and genotype-phenotype correlation.
1型面肩肱型肌营养不良症（FSHD1）的诊断依靠提示性的临床表现，并与4号染色体长臂35区（4q35）上D4Z4重复序列的杂合性收缩有关。
FSHD1的表型具有广泛的变异性，存在显著的家族间和家族内异质性。可区分出三种临床类型：与4至7个重复单位（RU）相关且病程多变的经典表型、具有1至3个RU的严重婴儿型以及与临界RU（8至10个RU）相关的轻度表型。在分子水平上，D4Z4收缩要具有致病性，需要发生在特定的染色体背景上，即4号染色体的4qA等位基因变体上。在大多数情况下，一旦临床怀疑患有FSHD，可通过使用Southern印迹法和与一组探针杂交的DNA检测在基因上确认诊断。然而，FSHD1的诊断仍然具有挑战性。首先，一些患者可能表现出具有高度局限性或不寻常症状的非典型表型。其次，FSHD的基因诊断存在潜在陷阱，会导致假阳性或假阴性结果。在没有基因确认的情况下，需要进行其他检查，主要是肌电图和肌肉活检，以排除其他诊断。在没有明确诊断且染色体无收缩的允许情况下，可能怀疑患有FSHD2。
分子梳技术是一种新技术，通过荧光显微镜可在拉伸的单根DNA纤维上的遗传背景下对D4Z4重复序列进行可视化和大小测定。该工具将改善FSHD患者的基因诊断。
FSHD1的诊断主要依靠临床特征。临床医生需要了解这种疾病的不寻常表现。家族内广泛的变异性以及基因型与表型之间缺乏良好的相关性给遗传咨询和预后带来了挑战。关于外显率和基因型 - 表型相关性，还需要更多的研究。
