Clinical spectrum and genotype-phenotype correlations in PRRT2 Italian patients,European Journal of Paediatric Neurology

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Clinical spectrum and genotype-phenotype correlations in PRRT2 Italian patients
European Journal of Paediatric Neurology ( IF 2.3 ) Pub Date : 2020-09-01 , DOI: 10.1016/j.ejpn.2020.06.005
Ganna Balagura ₁ , Antonella Riva ₁ , Francesca Marchese ₁ , Michele Iacomino ₂ , Francesca Madia ₂ , Thea Giacomini ₃ , Maria Margherita Mancardi ₃ , Elisabetta Amadori ₁ , Maria Stella Vari ₁ , Vincenzo Salpietro ₁ , Angelo Russo ₄ , Tullio Messana ₄ , Aglaia Vignoli ₅ , Valentina Chiesa ₆ , Lucio Giordano ₇ , Patrizia Accorsi ₈ , Lorella Caffi ₉ , Alessandro Orsini ₁₀ , Alice Bonuccelli ₁₀ , Margherita Santucci ₄ , Marilena Vecchi ₁₁ , Francesca Vanadia ₁₂ , Giuseppe Milito ₇ , Carlo Fusco ₁₃ , Giovanni Cricchiutti ₁₄ , Marilisa Carpentieri ₁₅ , Lucia Margari ₁₆ , Alberto Spalice ₁₇ , Francesca Beccaria ₁₈ , Fabio Benfenati ₁₉ , Federico Zara ₂₀ , Pasquale Striano ₁

Affiliation

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.
Medical Genetics Unit, IRCCS Giannina Gaslini Insitute, Genova, Italy.
Unit of Child Neuropsychiatry, Clinical and Surgical Neurosciences Department, IRCCS Istituto Giannina Gaslini, Genova, Italy.
UOC Neuropsichiatria Infantile, Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Bologna, Italy; IRCCS, Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy.
Child Neuropsychiatry Unit - Epilepsy Center, San Paolo Hospital, Milan, Italy; Department of Health Sciences, Università degli Studi di Milano, Milan, Italy.
Child Neuropsychiatry Unit - Epilepsy Center, San Paolo Hospital, Milan, Italy.
Child Neuropsychiatric Division, Spedali Civili, Brescia, Italy.
Clinical Pathology Unit, Pescara General Hospital, Pescara, Italy.
Neuropsichiatria Infantile, ASST Papa Giovanni XXIII, Bergamo, Italy.
Paediatric Neurology, Department of Paediatrics, University Hospital of Pisa, Pisa, Italy.
La Nostra Famiglia Association, University of Padova, Padova, Italy.
ARNAS Ospedali Civico Di Cristina Benfratelli, Palermo, Italy.
Department of Pediatrics, Child Neurology Unit, Azienda USL- IRCCS di Reggio Emilia, Reggio Emilia, Italy.
Department of Pediatrics, Pediatric Neurophysiology Laboratory, Azienda USL- IRCCS di Reggio Emilia, Reggio Emilia, Italy; Division of Pediatrics, Department of Medicine, University of Udine, Udine, Italy.
AOU "San Giovanni di Dio e Ruggi d'Aragona"- Servizio Neurologia Pediatrica PO "Santa Maria dell'Olmo", Cava dei Tirreni, SA, Italy.
Dipartimento di Scienze Mediche di Base, Neuroscienze ed Organi di Senso, Università degli Studi di Bari "Aldo Moro,", Bari, Italy.
Department of Pediatrics - Child Neurology Division - "Sapienza", University of Rome, Italy.
Epilepsy Center, Department of Child Neuropsychiatry, ASST Mantova, Mantua, Italy.
Istituto di Ricovero e Cura a Carattere Scientifico, Ospedale Policlinico San Martino, Genoa, Italy; Center for Synaptic Neuroscience and Technology, Istituto Italiano di Tecnologia, Genoa, Italy.
Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Italy; Medical Genetics Unit, IRCCS Giannina Gaslini Insitute, Genova, Italy.

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.

中文翻译：

PRRT2意大利患者的临床谱和基因型-表型相关性

Prrt2 是一种在轴突和突触前结构域表达的神经元特异性蛋白，参与突触神经递质释放和内在兴奋性的调节。PRRT2 突变导致一系列常染色体显性遗传性阵发性神经系统疾病，包括癫痫、运动障碍和偏瘫偏头痛，并显示出不完全外显和可变表达。我们在一组患有癫痫和/或阵发性运动机能障碍 (PKD) 的意大利患者中评估了 PRRT2 的诊断率，并评估了基因型-表型相关性。使用结构化问卷收集临床数据。55 名先证者中有 27 名 (49.1%) 携带 PRRT2 杂合致病变异，包括六种先前已知的基因型和一种新的错义突变。出生第一年的癫痫家族史和/或 PKD 强烈提示 PRRT2 致病性变异。与 PRRT2 阴性的癫痫患者相比，携带 PRRT2 致病性变异的癫痫患者表现出更早的癫痫发作和更频繁的集群。此外，我们还确定了具有非典型发病年龄的 PRRT2 致病变异的个体，即儿童期癫痫和婴儿期发病的 PKD。然而，特定 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病率表明其他因素参与调节 PRRT2 相关疾病的表达。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，这是从实验神经科学中出现的。

更新日期：2020-09-01

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