Abstract：
Pathogenic variants in PNPLA8 have been described either with congenital onset displaying congenital microcephaly, early onset epileptic encephalopathy and early lethality or childhood neurodegeneration with progressive microcephaly. Moreover, a phenotype comprising adulthood onset cerebellar ataxia and peripheral neuropathy was also reported. To our knowledge, only six patients with biallelic variants in PNPLA8 have been reported so far. Here, we report the clinical and molecular characterizations of three additional patients in whom exome sequencing identified a loss of function variant (c.1231C>T, p.Arg411Ter) in Family I and a missense variant (c.1559T>A, p.Val520Asp) in Family II in PNPLA8. Patient 1 presented with the congenital form of the disease while Patients 2 and 3 showed progressive microcephaly, infantile onset seizures, progressive cortical atrophy, white matter loss, bilateral degeneration of basal ganglia, and cystic encephalomalacia. Therefore, our results add the infantile onset as a new distinct phenotype of the disease and suggest that the site of the variant rather than its type is strongly correlated with the disease onset. In addition, these conditions demonstrate some overlapping features representing a spectrum with clinical features always aligning with different age of onset.
摘要：
已经描述了PNPLA8的致病变异，无论是先天性发病表现为先天性小头畸形，早发性癫痫性脑病和早期致死率或儿童神经变性伴进行性小头畸形。此外，还报道了一种表型,包括成年期发病的小脑共济失调和周围神经病变.据我们所知,到目前为止,只有6例PNPLA8双等位基因变异的患者被报道.这里,我们报告了另外三名患者的临床和分子特征，其中外显子组测序确定了功能变异的丧失（c.1231C>T，p.Arg411Ter）在家庭I和一个错觉变体（c.1559T>A，p.Val520Asp）在PNPLA8的家族II中。患者1表现为先天性疾病，而患者2和3表现为进行性小头畸形，婴儿发作性癫痫,进行性皮质萎缩,白质损失，双侧基底节变性，和囊性脑软化症.因此,我们的研究结果将婴儿发作作为该疾病的一种新的独特表型,并提示该变异的部位而非其类型与疾病发作密切相关.此外,这些情况显示出一些重叠的特征,这些特征代表了一个频谱,临床特征总是与不同的发病年龄相一致.
