Sun Guilian, Yao Fang, Tian Zhuoling, Ma Tianjiao, Yang Zhiliang
Department of Pediatrics, The First Hospital of China Medical University, No. 155 Nanjing North Street, Heping District, Shenyang, 110001, Liaoning Province, People's Republic of China.
BMC Med Genet. 2018 Oct 1;19(1):177. doi: 10.1186/s12881-018-0690-x.
Neuronal ceroid lipofuscinosis (NCLs) are lysosomal storage disorders characterized by seizures, motor impairment, and loss of vision. Ceroid lipofuscinosis (CLN) gene mutations are the cause, but NCL cases arising from CLN6 mutations have not been described in China to date. The CLN6 protein, which plays a role in lysosomal function, is an endoplasmic reticulum (ER) membrane protein with seven transmembrane (TM) domains. It has a cytosolic-facing amino terminal domain and a luminal-facing carboxyl terminal domain, with six loops between the TM domains.
Here we report a case involving a Chinese boy whose suspected diagnosis was a hereditary leukoencephalopathy, based on brain MRI imaging and epilepsy symptoms, language articulation disorders, ataxia, and unstable gait. The electroencephalogram showed epileptic discharges, and the brain MRI scan showed high signal intensity adjacent to the bilateral posterior horns of the lateral ventricles on T2-weighted images, along with cerebellar atrophy. Using next-generation sequencing for the genes in a panel for hereditary leukoencephalopathies, we detected a homozygous missense point mutation c.892G > A(p.Glu298Lys) in CLN6, and the variant was interpreted as pathogenic on in silico analysis. Absence of this mutation was confirmed in 259 controls. Late infantile NCL and secondary epilepsy were diagnosed, and oral sodium valproate was prescribed. The epilepsy was not well controlled, however, and the other signs had not improved at the 6-month follow-up. We also analyzed the loci of 31 CLN6 missense mutations, including those previously reported and the current one. We found that 22.6% (7/31) of the mutations are in the cytoplasmic domains, about 32.2% (10/31) are in the TM domains, and about 45.2% (14/31) are in the luminal domains. These mutations were mostly located in the TM3-TM4 loop (6/31), TM1-TM2 loop (4/31), and C-terminus (4/31), with none found in the TM4-TM5 loop, TM5-TM6 loop, or TM7.
We report the first case in China of NCL caused by a CLN6 mutation, expanding the genotype options for NCLs. In practice, NCLs generally are not the initial suspected diagnosis for such cases. Use of a gene sequencing panel for investigating unexplained seizures or leukoencephalopathies can help confirm the diagnosis.
神经元蜡样脂褐质沉积症（NCLs）是一种溶酶体贮积症，其特征为癫痫发作、运动障碍和视力丧失。蜡样脂褐质沉积症（CLN）基因突变是病因，但迄今为止，中国尚未报道由CLN6突变引起的NCL病例。CLN6蛋白在溶酶体功能中发挥作用，是一种具有七个跨膜（TM）结构域的内质网（ER）膜蛋白。它有一个面向胞质的氨基末端结构域和一个面向腔的羧基末端结构域，在TM结构域之间有六个环。
在此，我们报告一例涉及一名中国男孩的病例。根据脑部MRI成像以及癫痫症状、语言表达障碍、共济失调和步态不稳，其疑似诊断为遗传性白质脑病。脑电图显示有癫痫放电，脑部MRI扫描在T2加权图像上显示双侧侧脑室后角附近有高信号强度，伴有小脑萎缩。通过对遗传性白质脑病基因检测板中的基因进行二代测序，我们在CLN6中检测到一个纯合错义点突变c.892G＞A（p.Glu298Lys），该变异在计算机分析中被解释为致病性的。在259名对照中未发现该突变。诊断为晚期婴儿型NCL和继发性癫痫，并开具了口服丙戊酸钠。然而，癫痫未得到很好的控制，在6个月的随访中其他症状也没有改善。我们还分析了31个CLN6错义突变的位点，包括先前报道的和当前的这个突变。我们发现22.6%（7/31）的突变位于胞质结构域，约32.2%（10/31）位于TM结构域，约45.2%（14/31）位于腔结构域。这些突变大多位于TM3-TM4环（6/31）、TM1-TM2环（4/31）和C末端（4/31），在TM4-TM5环、TM5-TM6环或TM7中未发现。
我们报告了中国首例由CLN6突变引起的NCL病例，扩展了NCLs的基因型选择。在实际中，NCLs通常不是此类病例的初始疑似诊断。使用基因测序检测板来调查不明原因的癫痫发作或白质脑病有助于确诊。
