Tubulinopathies
Tubulinopathies, also known as tubulin-related cortical dysgenesis, are a group of heterogeneous autosomal dominant disorders that result in brain malformations caused by pathogenic variants of genes that encode tubulin.[1][2][3][4]
Individuals diagnosed with tubulinopathies typically display altered brain morphology such as "classic" lissencephaly (a thickening of the cortex with a posterior-to-anterior gradient of severity[1]), dysmorphic or hypertrophic basal ganglia (where these brain areas appear bulbous), and/or cerebellar hypoplasia/displasia.[4] Clinically, these individuals present with motor and cognitive impairments and epilepsy.[1][4] Mutations associated with tubulinopathies have been reported in several alpha- and beta-tubulin-encoding genes such as TUBA1A, TUBA8, TUBB2B, and TUBB3.[5][6]
Recent genetic studies have shown that heterozygous, missense mutations in α- and β-tubulin isotypes are sporatic in individuals carrying mutations in TUBA1A, TUBB5, and TUBB2B. Whereas TUBB3 mutations can be familiar or de novo.[1][5][7]
Tubulins
Tubulin proteins are important building blocks of the cytoskeleton that provide mechanical support for cells and assist in trafficking and anchoring of proteins and organelles. Tubulins are the structural subunit proteins that form microtubules[8]. The eukaryotic tubulin superfamily consist of alpha-, beta-, gamma-, delta-, epsilon-, and zeta-tubulin.[9][10] There exist several isotypes of tubulin that vary in the specific amino acid sequence, nucleotide sequences of untranslated regions, and tissue expression during different stages of development.[2] Tubulin (and therefore microtubules) have the capacity to stochastically cycle between polymerization and depolymerization, a feature called "dynamic instability" which allows for regulation of assembly or disassembly. Modulation of tubulin and microtubule expression is further regulated by microtubule associated proteins (MAPs).[7]
Disrupted MAP–tubulin interactions are often associated with developmental dysregulation of the brain and mutations in genes that encode these proteins form the genetic basis for tubulinopathies and the morphological features of the disorders.[2][11]
Clinical characteristics
Motor dysfunction
Due to the large heterogeneity in tubulinopathies impacting brain development, difficulties in motor control in individuals diagnosed with these disorders often vary clinically.
A case report by Geiger et al. reported a 31 year old Caucasian woman with myoclonus-dystonia carrying a TUBB2B mutation, presenting with a an involuntary left head tilt and myoclinic jerks in the neck, trunk, and upper extremities, as well as high frequency tremors in the left hand.[12] Neuroimaging showed asymmetric pachygyria and dysmorphic basal ganglia, and neurological tests were positive for mild cognitive impairment and skeletal anomalies.
In a 2025 retrospective study, Ikegawa and colleagues reviewed medical records of tubulinopathy patients treated at Kanagawa Children's Medical Center from January 2000 to May 2022. A substantial number of patients had no or delayed gait acquisition, and those with the TUBB4A variant were unable to walk and did not have neck stability, and were without speech. The authors suggested that cortical dysplasia in tubulinopathies may reflect a higher severity of developmental delay due to impaired neuronal migration.[13]
A case review of several patients by Poirier et al. showed tubulinopathy patients often presented with axial hypotonia (reduced muscle tone in the neck and trunk) and spastic diplegia or tetraplegia (a subset of cerebral palsy that is defined by limb spasticity).[14]
Cognitive impairment
Cognitive impairment in individuals with tubulinopathies is highly present, and, like motor symptoms, vary from patient to patient.
Because proper cytoskeletal arrangement in the developing brain is important for neuronal differentiation and migration, mutations in tubulin-encoding genes result in morphological abnormalities that contribute to neurological impairments.
For example, a case study presented by Yuen and colleagues discussed a 10-year old female that passed early developmental milestones, but intellectual disability was apparent at six years old and was two years behind her peers.[15] Ultrasound during pregnancy noted antenatal microcephaly and by age ten was two standard-deviations below the mean for head circumference. The patient was reported to have a TUBG1 mutation. However, the neurological examination, other than the delayed milestones, were "otherwise unremarkable", with no motor deficits or epilepsy, and mild facial dysmorphia.
Another patient with a de novo TUBG1 mutation (reported by the same group) presented much differently, however. A 13-month old with noted microcephaly on ultrasound during pregnancy experienced a seizure with left-sided clonic activity and secondary bilateral synchrony and oxygen desaturation during the first hour of life.[15] The patient continued to experience several seizures over the next few months generally associated with feeding. At 13 months, the patient was not yet rolling or sitting independently, but babbled and was able to visually fix and follow.
A meta-analysis performed by Pavone and colleagues noted several patients with TUBA1A mutations that presented with Hirschsprung disease and inappropriate antidiuretic hormone secretion, severe intellectual disability, and absence of language.[16]
An animal model of a tubulinopathy found cognitive impairments and dysregulated neuronal excitability in mice exhibiting the brain dimple (brdp) mutation. Heterozygous Tubb2bbrdp/+ mice showed impairments in learning, memory, and reduced long-term potentiation in the hippocampal CA1 region, as well as general morphological disruptions throughout the hippocampus.[17]
Epilepsy
Epilepsies are common in tubulinopathy diagnoses.
Molecular determinants
References
- ↑ 1.0 1.1 1.2 1.3 Bahi-Buisson, Nadia; Maillard, Camille (16 September 2021). "Tubulinopathies Overview". GeneReviews® [Internet]. University of Washington, Seattle. PMID 27010057.
- ↑ 2.0 2.1 2.2 Gonçalves, Fabrício G.; Freddi, Tomás de Andrade L.; Taranath, Ajay; Lakshmanan, Rahul; Goetti, Robert; Feltrin, Fabricio S.; Mankad, Kshitij; Teixeira, Sara R.; Hanagandi, Prasad B.; Arrigoni, Filippo (December 2018). "Tubulinopathies". Topics in Magnetic Resonance Imaging. 27 (6): 395–408. doi:10.1097/RMR.0000000000000188. ISSN 0899-3459. PMID 30516692.
- ↑ Brar, Bobby K.; Thompson, Marisa Gilstrop; Vora, Neeta L.; Gilmore, Kelly; Blakemore, Karin; Miller, Kristen A.; Giordano, Jessica; Dufke, Andreas; Wong, Beatrix; Stover, Samantha; Lianoglou, Billie; Van den Veyver, Ignatia; Dempsey, Esther; Rosner, Mara; Chong, Karen; Chitayat, David; Sparks, Teresa N.; Norton, Mary E.; Wapner, Ronald; Baranano, Kristin; Jelin, Angie C. (December 2022). "Prenatal phenotyping of fetal tubulinopathies: A multicenter retrospective case series". Prenatal Diagnosis. 42 (13): 1686–1693. doi:10.1002/pd.6269. ISSN 1097-0223. PMC 9805891 Check
|pmc=value (help). PMID 36403095 Check|pmid=value (help). - ↑ 4.0 4.1 4.2 Durizot, Meghane; Burglen, Lydie; Garel, Catherine; Blondiaux, Eléonore; Riquet, Audrey; Floret, Valentine; Desportes, Vincent; Haanpää, Maria; Valenzuela, Maria Irene; Pinto, Anna Maria; Renieri, Alessandra; Vanneste, Michiel; Devriendt, Koen; de Waele, Liesbeth; Guilbaud, Lucie; Jouannic, Jean-Marie; Harion, Madeleine; Billette de Villemeur, Thierry; Rodriguez, Diana; Lacaze, Emmanuelle; Milh, Mathieu; Cloarec, Robin; Afenjar, Alexandra; Héron, Delphine; Mignot, Cyril; Valence, Stéphanie (September 2025). "Attenuated Clinical Forms of Tubulinopathies in Children and Adults: A Series of 24 Individuals". Pediatric Neurology. 170: 49–57. doi:10.1016/j.pediatrneurol.2025.06.003. PMID 40614697 Check
|pmid=value (help). - ↑ 5.0 5.1 Bahi-Buisson, Nadia; Poirier, Karine; Fourniol, Franck; Saillour, Yoann; Valence, Stéphanie; Lebrun, Nicolas; Hully, Marie; Fallet Bianco, Catherine; Boddaert, Nathalie; Elie, Caroline; Lascelles, Karine; Souville, Isabelle; Beldjord, Cherif; Chelly, Jamel (1 June 2014). "The wide spectrum of tubulinopathies: what are the key features for the diagnosis?". Brain. 137 (6): 1676–1700. doi:10.1093/brain/awu082. PMID 24860126.
- ↑ Maillard, Camille; Roux, Charles Joris; Charbit-Henrion, Fabienne; Steffann, Julie; Laquerriere, Annie; Quazza, Floriane; Buisson, Nadia Bahi (15 March 2023). "Tubulin mutations in human neurodevelopmental disorders". Seminars in Cell & Developmental Biology. 137: 87–95. doi:10.1016/j.semcdb.2022.07.009. PMID 35915025 Check
|pmid=value (help). - ↑ 7.0 7.1 Hoff, Katelyn J.; Neumann, Andrew J.; Moore, Jeffrey K. (2 November 2022). "The molecular biology of tubulinopathies: Understanding the impact of variants on tubulin structure and microtubule regulation". Frontiers in Cellular Neuroscience. 16. doi:10.3389/fncel.2022.1023267. PMID 36406756 Check
|pmid=value (help). Unknown parameter|article-number=ignored (help) - ↑ Dustin, Pierre (1984). "General Physiology of Tubulins and Microtubules". Microtubules. Springer. pp. 94–126. doi:10.1007/978-3-642-69652-7_6. ISBN 978-3-642-69652-7. Search this book on
- ↑ Oakley, Berl R (December 2000). "An abundance of tubulins". Trends in Cell Biology. 10 (12): 537–542. doi:10.1016/s0962-8924(00)01857-2. PMID 11121746.
- ↑ McKean, Paul G.; Vaughan, Sue; Gull, Keith (1 August 2001). "The extended tubulin superfamily". Journal of Cell Science. 114 (15): 2723–2733. doi:10.1242/jcs.114.15.2723. PMID 11683407.
- ↑ Dent, Erik W.; Kalil, Katherine (15 December 2001). "Axon Branching Requires Interactions between Dynamic Microtubules and Actin Filaments". The Journal of Neuroscience. 21 (24): 9757–9769. doi:10.1523/JNEUROSCI.21-24-09757.2001. PMC 6763027 Check
|pmc=value (help). PMID 11739584. - ↑ Geiger, Joshua T.; Schindler, Alice B.; Blauwendraat, Cornelis; Singer, Harvey S.; Scholz, Sonja W. (31 August 2017). "TUBB2B Mutation in an Adult Patient with Myoclonus-Dystonia". Case Reports in Neurology. 9 (2): 216–221. doi:10.1159/000479788. PMID 28966590.
- ↑ Ikegawa, Tamaki; Osada, Kana; Ikeda, Azusa; Tsuyusaki, Yu; Tsuji, Megumi; Iai, Mizue; Aida, Noriko; Kurosawa, Kenji; Matsumoto, Naomichi; Goto, Tomohide (June 2025). "Clinical characteristics and radiological features of tubulinopathy: A single-center retrospective study in Japan". Brain and Development. 47 (3): 104356. doi:10.1016/j.braindev.2025.104356. PMID 40179460 Check
|pmid=value (help). - ↑ Poirier, Karine; Saillour, Yoann; Bahi-Buisson, Nadia; Jaglin, Xavier H.; Fallet-Bianco, Catherine; Nabbout, Rima; Castelnau-Ptakhine, Laetitia; Roubertie, Agathe; Attie-Bitach, Tania; Desguerre, Isabelle; Genevieve, David; Barnerias, Christine; Keren, Boris; Lebrun, Nicolas; Boddaert, Nathalie; Encha-Razavi, Féréchté; Chelly, Jamel (15 November 2010). "Mutations in the neuronal β-tubulin subunit TUBB3 result in malformation of cortical development and neuronal migration defects". Human Molecular Genetics. 19 (22): 4462–4473. doi:10.1093/hmg/ddq377. PMID 20829227.
- ↑ 15.0 15.1 Yuen, Yue T. K.; Guella, Ilaria; Roland, Elke; Sargent, Michael; Boelman, Cyrus (31 May 2019). "Case reports: novel TUBG1 mutations with milder neurodevelopmental presentations". BMC Medical Genetics. 20 (1): 95. doi:10.1186/s12881-019-0827-6. ISSN 1471-2350. PMC 6545025 Check
|pmc=value (help). PMID 31151415. - ↑ Pavone, Piero; Striano, Pasquale; Cacciaguerra, Giovanni; Marino, Simona Domenica; Parano, Enrico; Pappalardo, Xena Giada; Falsaperla, Raffaele; Ruggieri, Martino (8 September 2023). "Case report: Structural brain abnormalities in TUBA1A-tubulinopathies: a narrative review". Frontiers in Pediatrics. 11. doi:10.3389/fped.2023.1210272. ISSN 2296-2360. PMID 37744437 Check
|pmid=value (help). Unknown parameter|article-number=ignored (help) - ↑ Stottmann, Rolf W.; Driver, Ashley; Gutierrez, Arnold; Skelton, Matthew R.; Muntifering, Michael; Stepien, Christopher; Knudson, Luke; Kofron, Matthew; Vorhees, Charles V.; Williams, Michael T. (February 2017). "A heterozygous mutation in tubulin, beta 2B ( Tubb2b ) causes cognitive deficits and hippocampal disorganization". Genes, Brain and Behavior. 16 (2): 250–259. doi:10.1111/gbb.12327.
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