Neurogenetics DNA Diagnostic Laboratory, Department of Neurology, and Center for Human Genetic Research, Massachusetts General Hospital, Simches Research Building, Boston, MA 02114, USA.
Neurology. 2010 Feb 16;74(7):565-71. doi: 10.1212/WNL.0b013e3181cff70d.
To explore a potential expansion of the phenotypic and genotypic characteristics of Finnish variant late-infantile neuronal ceroid lipofuscinosis (NCL), we screened a collection of 47 patients with clinically diagnosed NCL in whom no molecular diagnosis had been made.
We used PCR amplification of genomic DNA, followed by fluorescent-labeled dideoxy-nucleotide chain termination sequencing and multiplex ligation-dependent probe amplification, to screen our cohort of patients for mutations in CLN5. We collected ethnic background, clinical, and pathologic information, as available, to clarify the breadth of CLN5 disease expression and to explore possible genotype-phenotype correlations.
We identified 10 patients with pathogenic CLN5 mutations, including 11 mutations not previously described: 4 missense, 5 out-of-frame insertion/deletion mutations, and 2 large intragenic deletions. We also documented 3 previously reported CLN5 mutations. The age at disease onset in this cohort is predominantly juvenile rather than late infantile. Importantly, we have identified 2 adult-onset patients who share a common pathogenic allele. The majority of patients presented with motor and visual impairments and not seizures. In those patients with available longitudinal data, most had progressed to global neurodevelopmental and visual failure with seizures within 1 to 4 years.
Our study suggests that CLN5 mutations 1) are more common in patients with neuronal ceroid lipofuscinosis (NCL) than previously reported, 2) are found in non-Finnish NCL patients of broad ethnic diversity, and 3) can be identified in NCL patients with disease onset in adult and juvenile epochs. CLN5 genetic testing is warranted in a wider population with clinical and pathologic features suggestive of an NCL disorder.
为了探索芬兰变异型晚发性神经元蜡样脂褐质沉积症（NCL）表型和基因型特征的潜在扩展，我们筛选了 47 名经临床诊断为 NCL 但未进行分子诊断的患者的样本。
我们使用基因组 DNA 的 PCR 扩增，然后进行荧光标记的双脱氧核苷酸链终止测序和多重连接依赖性探针扩增，对我们的患者队列进行 CLN5 基因突变筛查。我们收集了可用的种族背景、临床和病理信息，以阐明 CLN5 疾病表达的广度，并探索可能的基因型-表型相关性。
我们鉴定出 10 名患者存在致病性 CLN5 突变，包括 11 种以前未描述的突变：4 种错义突变、5 种移码插入/缺失突变和 2 种大片段基因内缺失。我们还记录了 3 种以前报道的 CLN5 突变。本队列的发病年龄主要为青少年而非晚婴期。重要的是，我们发现了 2 名具有共同致病性等位基因的成年发病患者。大多数患者表现为运动和视力障碍，而不是癫痫发作。在那些具有可用纵向数据的患者中，大多数在 1 至 4 年内进展为全面神经发育和视觉衰竭伴癫痫发作。
我们的研究表明，CLN5 突变 1）在神经元蜡样脂褐质沉积症（NCL）患者中比以前报道的更为常见，2）在具有广泛种族多样性的非芬兰 NCL 患者中发现，3）可以在发病年龄在成人和青少年期的 NCL 患者中识别。CLN5 基因检测在具有临床和病理特征提示 NCL 障碍的更广泛人群中是必要的。
