Klevering B Jeroen, Deutman August F, Maugeri Alessandra, Cremers Frans P M, Hoyng Carel B
Department of Ophthalmology, University Medical Centre Nijmegen, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands.
Graefes Arch Clin Exp Ophthalmol. 2005 Feb;243(2):90-100. doi: 10.1007/s00417-004-1079-4. Epub 2004 Dec 22.
The majority of studies on the retina-specific ATP-binding cassette transporter (ABCA4) gene have focussed on molecular genetic analysis; comparatively few studies have described the clinical aspects of ABCA4-associated retinal disorders. In this study, we demonstrate the spectrum of retinal dystrophies associated with ABCA4 gene mutations.
Nine well-documented patients representing distinct phenotypes in the continuum of ABCA4-related disorders were selected. All patients received an extensive ophthalmologic evaluation, including kinetic perimetry, fluorescein angiography, and electroretinography (ERG). Mutation analysis had been performed previously with the genotyping microarray (ABCR400 chip) and/or single-strand conformation polymorphism analysis in combination with direct DNA sequencing.
In all patients, at least one pathologic ABCA4 mutation was identified. Patient 10034 represented the mild end of the phenotypic spectrum, demonstrating exudative age-related macular degeneration (AMD). Patient 24481 received the diagnosis of late-onset fundus flavimaculatus (FFM), patient 15168 demonstrated the typical FFM phenotype, and patient 19504 had autosomal recessive Stargardt disease (STGD1). Patients 11302 and 7608 exhibited progression from FFM/STGD1 to cone-rod dystrophy (CRD). A more typical CRD phenotype was found in patients 15680 and 12608. Finally, the most severe ABCA4-associated phenotype was retinitis pigmentosa (RP) in patient 11366. This phenotype was characterised by extensive atrophy with almost complete loss of peripheral and central retinal functions.
We describe nine patients during different stages of disease progression; together, these patients form a continuum of ABCA4-associated phenotypes. Besides characteristic disorders such as FFM/STGD1, CRD and RP, intermediate phenotypes may be encountered. Moreover, as the disease progresses, marked differences may be observed between initially comparable phenotypes. In contrast, distinctly different phenotypes may converge to a similar final stage, characterised by extensive chorioretinal atrophy and very low visual functions. The identified ABCA4 mutations in most, but not all, patients were compatible with the resulting phenotypes, as predicted by the genotype-phenotype model for ABCA4-associated disorders. With the advent of therapeutic options, recognition by the general ophthalmologist of the various retinal phenotypes associated with ABCA4 mutations is becoming increasingly important.
大多数关于视网膜特异性ATP结合盒转运蛋白（ABCA4）基因的研究都集中在分子遗传学分析上；相对较少的研究描述了ABCA4相关视网膜疾病的临床情况。在本研究中，我们展示了与ABCA4基因突变相关的视网膜营养不良谱系。
选择了9例记录完整的患者，他们代表了ABCA4相关疾病连续体中的不同表型。所有患者均接受了全面的眼科评估，包括动态视野检查、荧光素血管造影和视网膜电图（ERG）。先前已通过基因分型微阵列（ABCR400芯片）和/或单链构象多态性分析结合直接DNA测序进行了突变分析。
在所有患者中，均鉴定出至少一种病理性ABCA4突变。患者10034代表表型谱系的轻度端，表现为渗出性年龄相关性黄斑变性（AMD）。患者24481被诊断为迟发性眼底黄色斑点症（FFM），患者15168表现出典型的FFM表型，患者19504患有常染色体隐性遗传性黄斑营养不良（STGD1）。患者11302和7608表现出从FFM/STGD1进展为锥杆营养不良（CRD）。在患者15680和12608中发现了更典型的CRD表型。最后，患者11366中最严重的ABCA4相关表型是色素性视网膜炎（RP）。该表型的特征是广泛萎缩，几乎完全丧失周边和中央视网膜功能。
我们描述了9例处于疾病进展不同阶段患者；这些患者共同构成了ABCA4相关表型的连续体。除了FFM/STGD1、CRD和RP等特征性疾病外，可能会遇到中间表型。此外，随着疾病进展，在最初可比的表型之间可能会观察到明显差异。相反，明显不同的表型可能会汇聚到一个相似的终末期阶段，其特征是广泛的脉络膜视网膜萎缩和极低的视功能。如ABCA4相关疾病的基因型-表型模型所预测的，在大多数但并非所有患者中鉴定出的ABCA4突变与所产生的表型相符。随着治疗选择的出现，普通眼科医生对与ABCA4突变相关的各种视网膜表型的认识变得越来越重要。
