Attenuated Clinical Forms of Tubulinopathies in Children and Adults: A Series of 24 Individuals

IF 2.1 3区医学 Q2 CLINICAL NEUROLOGY

Pediatric neurology Pub Date : 2025-06-11 DOI:10.1016/j.pediatrneurol.2025.06.003

Meghane Durizot MD , Lydie Burglen MD, PhD , Catherine Garel MD, PhD , Eléonore Blondiaux MD, PhD , Audrey Riquet MD , Valentine Floret MD , Vincent Desportes MD, PhD , Maria Häänpaa MD, PhD , Maria Irene Valenzuela MD , Anna Maria Pinto MD, PhD , Alessandra Renieri MD, PhD , Michiel Vanneste MD , Koen Devriendt MD, PhD , Liesbeth de Waele MD, PhD , Lucie Guilbaud MD, PhD , Jean-Marie Jouannic MD, PhD , Madeleine Harion MD , Thierry Billette de Villemeur MD, PhD , Diana Rodriguez MD, PhD , Emmanuelle Lacaze MD , Stéphanie Valence MD, PhD

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引用次数: 0

Abstract

Background: Tubulinopathies are neurodevelopmental disorders caused by pathogenic variants in tubulin-encoding genes, typically presenting with intellectual disability (ID), epilepsy, motor impairments, and distinct brain malformations. While most cases are de novo and severe, recent reports suggest the existence of milder imaging and clinical phenotypes, including familial cases with attenuated symptoms.

Methods: Through international collaboration, clinical, imaging, and molecular data were collected from 24 individuals (≥4 years old) across 16 families with pathogenic or likely pathogenic variants in TUBA1A, TUBB2B, TUBB3, TUBB, or TUBB2A. Patients were selected based on absence of ID and availability of brain MRI. Genetic inheritance patterns and genotype–phenotype correlations were analyzed.

Results: Fifteen patients were identified through fetal or pediatric imaging and nine through familial investigations. No cases exhibited severe cortical gyration anomalies. TUBB3 was the most frequently mutated gene (12/24, 50%), and 7 out of 14 total variants were inherited. Two recurrent variants, TUBB3 p.(Pro357Leu) and TUBB p.(Asn52Ser), were associated with non-ID phenotypes in both the current cohort and literature.

Conclusions: This study broadens the spectrum of tubulinopathies to include mild imaging phenotypes with attenuated clinical features in children and adults. Absence of major cortical malformations, inherited mutations, and specific genetic variants may serve as favorable prognostic markers. These findings have important implications for genetic counseling, particularly in prenatal cases.

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儿童和成人小管病变的减毒临床形式：一系列24个人

背景：小管蛋白病是由小管蛋白编码基因的致病性变异引起的神经发育障碍，通常表现为智力残疾（ID）、癫痫、运动障碍和明显的脑畸形。虽然大多数病例为新发且严重，但最近的报告表明存在较轻的影像学和临床表型，包括症状减轻的家族性病例。方法：通过国际合作，收集来自16个TUBA1A、TUBB2B、TUBB3、TUBB或TUBB2A致病性或可能致病性变异家族的24名个体（≥4岁）的临床、影像学和分子数据。患者的选择基于ID的缺失和脑MRI的可用性。分析遗传模式和基因型-表型相关性。结果：15例患者通过胎儿或儿童影像学确诊，9例通过家族性调查确诊。没有病例表现出严重的皮质旋转异常。TUBB3是最常见的突变基因（12/24,50%），14个变异中有7个是遗传的。在当前的队列和文献中，两个复发变异体，tubb3p .（Pro357Leu）和tubbp .（Asn52Ser）与非id表型相关。结论：这项研究扩大了小管病变的范围，包括儿童和成人的轻度影像学表型和减弱的临床特征。没有主要的皮质畸形、遗传突变和特定的基因变异可以作为有利的预后标志。这些发现对遗传咨询具有重要意义，特别是在产前情况下。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Pediatric neurology 医学-临床神经学

CiteScore

4.80

自引率

2.60%

发文量

176

审稿时长

78 days

期刊介绍： Pediatric Neurology publishes timely peer-reviewed clinical and research articles covering all aspects of the developing nervous system. Pediatric Neurology features up-to-the-minute publication of the latest advances in the diagnosis, management, and treatment of pediatric neurologic disorders. The journal''s editor, E. Steve Roach, in conjunction with the team of Associate Editors, heads an internationally recognized editorial board, ensuring the most authoritative and extensive coverage of the field. Among the topics covered are: epilepsy, mitochondrial diseases, congenital malformations, chromosomopathies, peripheral neuropathies, perinatal and childhood stroke, cerebral palsy, as well as other diseases affecting the developing nervous system.