Pediatric Neurology and Muscular Diseases Unit, IRCCS "G. Gaslini" Institute, Genova, Italy; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Italy.
Pediatric Neurology and Muscular Diseases Unit, IRCCS "G. Gaslini" Institute, Genova, Italy; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Italy.
Eur J Paediatr Neurol. 2020 Sep;28:193-197. doi: 10.1016/j.ejpn.2020.06.005. Epub 2020 Jun 23.
Prrt2 is a neuron-specific protein expressed at axonal and pre-synaptic domains, involved in synaptic neurotransmitter release and modulation of intrinsic excitability. Mutations in PRRT2 cause a spectrum of autosomal dominant paroxysmal neurological disorders including epilepsy, movement disorders, and hemiplegic migraine and show incomplete penetrance and variable expressivity. We assessed the diagnostic rate of PRRT2 in a cohort of Italian patients with epilepsy and/or paroxysmal kinesigenic dyskinesia (PKD) and evaluated genotype-phenotype correlations. Clinical data were collected using a structured questionnaire. Twenty-seven out of 55 (49.1%) probands carried PRRT2 heterozygous pathogenic variants, including six previously known genotypes and one novel missense mutation. A family history of epilepsy starting in the first year of life and/or PKD was strongly suggestive of a PRRT2 pathogenic variant. Epilepsy patients harbouring PRRT2 pathogenic variants showed earlier seizure onset and more frequent clusters compared with PRRT2-negative individuals with epilepsy. Moreover, we did also identify individuals with PRRT2 pathogenic variants with atypical age at onset, i.e. childhood-onset epilepsy and infantile-onset PKD. However, the lack of a clear correlation between specific PRRT2 genotypes and clinical manifestations and the high incidence of asymptomatic carriers suggest the involvement of additional factors in modulating expressivity of PRRT2-related disorders. Finally, our study supports the pleiotropic and multifaceted physiological role of PRRT2 gene which is emerging from experimental neuroscience.
PRRT2 是一种在轴突和突触前域表达的神经元特异性蛋白，参与突触神经递质释放和固有兴奋性的调节。PRRT2 突变导致一系列常染色体显性阵发性神经障碍，包括癫痫、运动障碍和偏瘫性偏头痛，表现为不完全外显和可变表达。我们评估了 PRRT2 在意大利癫痫和/或阵发性运动诱发性运动障碍（PKD）患者队列中的诊断率，并评估了基因型-表型相关性。临床数据使用结构化问卷收集。55 名先证者中有 27 名（49.1%）携带 PRRT2 杂合致病性变异，包括 6 种先前已知的基因型和 1 种新的错义突变。家族史中有婴儿期起病的癫痫和/或 PKD，强烈提示存在 PRRT2 致病性变异。携带 PRRT2 致病性变异的癫痫患者比 PRRT2 阴性的癫痫患者发病更早，发作更频繁。此外，我们还发现了携带 PRRT2 致病性变异的个体，其发病年龄不典型，即儿童期起病的癫痫和婴儿期起病的 PKD。然而，特定的 PRRT2 基因型与临床表现之间缺乏明确的相关性，以及无症状携带者的高发生率，表明在调节 PRRT2 相关疾病的表现型方面存在其他因素的参与。最后，我们的研究支持 PRRT2 基因的多效性和多方面的生理作用，这一作用正从实验神经科学中显现出来。
