Hosseini Bereshneh Ali, Garshasbi Masoud
Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
J Med Case Rep. 2018 Sep 25;12(1):281. doi: 10.1186/s13256-018-1788-7.
The neuronal ceroid lipofuscinoses are a group of neurodegenerative, lysosomal storage disorders. They are inherited as an autosomal recessive pattern with the exception of adult neuronal ceroid lipofuscinosis, which can be inherited in either an autosomal recessive or an autosomal dominant manner. The neuronal ceroid lipofuscinoses are characterized by accumulation of autofluorescent lipopigments in the cells and one of the most important pathological manifestations is ceroid accumulation in the lysosomes. Various types of neuronal ceroid lipofuscinoses are categorized based on the clinical manifestations and the genes involved. Accumulatively, 15 different genes have been found so far to be implicated in the pathogenesis of at least nine different types of neuronal ceroid lipofuscinoses, which result in similar pathological and clinical manifestations.
A 5-year-old Iranian boy affected by a neurodegenerative disorder with speech problems, lack of concentration, walking disability at age of 4 years leading to quadriplegia, spontaneous laughing, hidden seizure, clumsiness, psychomotor delay, and vision deterioration at age of 5 years, which could be the consequence of macular dystrophy, was referred to us for genetic testing. Trio whole exome sequencing, Sanger validation, and segregation analysis discovered a novel in-frame small deletion c.325_339del (p.Val109_Ile113del) in MFSD8 gene associated with neuronal ceroid lipofuscinosis type 7.
The deletion found in this patient affects the exon 5 of this gene which is the region encoding transmembrane domain. Sequencing analysis in this family has shown that the index is homozygous for 15 base pairs in-frame deletion, his uncle has normal homozygous, and his parents are heterozygous. This pattern of mutation inheritance and the signs and symptoms observed in the affected male of this family are compatible with what is described in the literature for neuronal ceroid lipofuscinosis type 7 and, therefore, suggest that the MFSD8 gene deletion found in this study is most probably the cause of disease in this family.
神经元蜡样脂褐质沉积症是一组神经退行性溶酶体贮积症。除成人神经元蜡样脂褐质沉积症可呈常染色体隐性或显性遗传外，其余类型均以常染色体隐性方式遗传。神经元蜡样脂褐质沉积症的特征是细胞内自发荧光脂色素的积累，最重要的病理表现之一是溶酶体内蜡样物质的积累。根据临床表现和相关基因对各种类型的神经元蜡样脂褐质沉积症进行分类。迄今为止，累计发现15种不同基因与至少9种不同类型的神经元蜡样脂褐质沉积症的发病机制有关，这些类型导致相似的病理和临床表现。
一名5岁伊朗男孩患有神经退行性疾病，有言语问题、注意力不集中、4岁时出现行走障碍并导致四肢瘫痪、自发发笑、隐匿性癫痫、动作笨拙、精神运动发育迟缓，5岁时出现视力下降，可能是黄斑营养不良的结果，前来我们这里进行基因检测。三联体全外显子组测序、桑格验证和分离分析发现MFSD8基因存在一个新的框内小缺失c.325_339del（p.Val109_Ile113del），与7型神经元蜡样脂褐质沉积症相关。
该患者中发现的缺失影响该基因编码跨膜结构域的第5外显子。对该家族的测序分析表明，先证者为15个碱基对的框内缺失纯合子，其叔叔为正常纯合子，其父母为杂合子。这种突变遗传模式以及在该家族患病男性中观察到的体征和症状与文献中描述的7型神经元蜡样脂褐质沉积症相符，因此表明本研究中发现的MFSD8基因缺失很可能是该家族疾病的病因。
