Attenuated Clinical Forms of Tubulinopathies in Children and Adults: A Series of 24 Individuals
Year: 2025
Type: article
Study design: Observational Study
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.
Source: Pediatric Neurology
Authors: Meghane Durizot, Lydie Burglen, Catherine Garel, Eléonore Blondiaux, Audrey Riquet, Valentine Floret, Vincent Desportes, Maria Haanpää, Maria Irene Valenzuela, Anna Maria Pinto, Alessandra Renieri, Michiel Vanneste, Koen Devriendt, Liesbeth de Waele, Lucie Guilbaud, Jean-Marie Jouannic, Madeleine Harion, Thierry Billette de Villemeur, Diana Rodriguez, Emmanuelle Lacaze, Mathieu Milh, Robin Cloarec, Alexandra Afenjar, Delphine Héron, Cyril Mignot, Stéphanie Valence
Institutions: Sorbonne Université, Hôpital Armand-Trousseau, Assistance Publique – Hôpitaux de Paris, Université Catholique de Lille, Groupe Hospitalier de l'Institut Catholique de Lille, Centre Hospitalier Universitaire de Lille, Hôpital Roger Salengro, Université de Lyon, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Turku University Hospital, Vall d'Hebron Hospital Universitari, University of Siena, Ospedale Santa Maria alle Scotte, Azienda Ospedaliera Universitaria Senese, Universitair Ziekenhuis Leuven, Aix-Marseille Université, Hôpital de la Timone, Assistance Publique Hôpitaux de Marseille, Pitié-Salpêtrière Hospital
Language: English
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,520
OpenAlex ID: W4411196471