Tubulinopathy Presenting as Developmental and Epileptic Encephalopathy

Abstract

Tubulin proteins play a role in the cortical development. Mutations in the tubulin genes affect patients with brain malformations. The present report describes two cases of developmental and epileptic encephalopathy (DEE) due to tubulinopathy. Case 1, a 23-year-old boy, was found to have a brain malformation with moderate ventriculomegaly prenatally. Hypotonia was noted at birth. Seizures were noted on the 1st day with multifocal discharges on the EEGs, which became intractable to many anticonvulsants. Brain MRI showed marked dilated ventricles and pachy/polymicrogyri. He became a victim of DEE. A de novo mutation in TUBB2B was proven through next-generation sequencing (NGS). Case 2, a mature male baby, began to have myoclonic jerks of his limbs 4 h after birth. EEG showed focal sharp waves from central and temporal regions. Brain MRI showed lissencephaly, type I. The seizures were refractory initially. A de novo mutation in TUBA1A was proven at the 6th week through NGS. He showed the picture of DEE at 1 year and 2 months of age. The clinical features of the tubulinopathies include motor delay, intellectual disabilities, epilepsy, and other deficits. Our cases demonstrated the severe form of tubulinopathy due to major tubulin gene mutations. NGS makes the early identification of genetic etiology possible for clinical evaluation.

Prenatal phenotyping of fetal tubulinopathies: A multicenter retrospective case series

“…In one case, MRI at 21 weeks 5 days was notable for lateral ventriculomegaly and a dysplastic z-shaped brainstem, and in the other case, ventriculomegaly was present in association with asymmetry of the brainstem and cerebellum. 5,6 Interestingly, in case 6 in our series, a z-shaped configuration of the brainstem was also present, suggesting that this may be an ancillary prenatal finding of the tubulinopathies. Additionally, although prenatal ventriculomegaly was seen in the vast majority of cases in our series, it is notable that the ventriculomegaly was not isolated in any case, underlying the importance of evaluating for additional CNS malformations when fetal ventriculomegaly is identified.…”

“…Prenatal ventriculomegaly was noted to be present in two prior cases of tubulinopathies in the literature. In one case, MRI at 21 weeks 5 days was notable for lateral ventriculomegaly and a dysplastic z‐shaped brainstem, and in the other case, ventriculomegaly was present in association with asymmetry of the brainstem and cerebellum 5,6 . Interestingly, in case 6 in our series, a z‐shaped configuration of the brainstem was also present, suggesting that this may be an ancillary prenatal finding of the tubulinopathies.…”

Loss of symmetric cell division of apical neural progenitors drivesDENND5A-related developmental and epileptic encephalopathy

“…Variants in tubulin genes also result in overlapping phenotypes 48 , but our cases lack the classic dysgyria pattern and instead are typically observed in the context of occipital pachygyria and differ in that our cases are associated with calcifications. Moreover, it seems that our cases have more severe basal ganglia abnormalities when compared with the typical imaging presentations associated with TUBA1A, TUBB2A, TUBB2B, TUBB3, and TUBG1 [49][50][51] . Variants in LIS1, encoding a protein involved in neuronal migration, results most frequently in a posterior gradient of lissencephaly, without calcifications, and variable degrees of corpus callosum size including thin, normal, and thicker than normal tracts 52,53 .…”

Lissencephaly caused by a de novo mutation in tubulin TUBA1A: a case report and literature review

“…Tubulin is a structural subunit protein that forms microtubules, and its highly dynamic cytoskeletal structure participates in a variety of cellular functions ( 6 – 8 ) and plays a key role in cortical development and stratification ( 9 ). Since it was first described in 2007 ( 1 ), at least eight gene variants have been reported clinically, including α-tubulin ( TUBA1A , TUBA8 ), β-tubulin ( TUBB2A , TUBB2B , TUBB3 , TUBB4A , TUBB ), and γ-tubulin ( TUBG1 ) ( 10 , 11 ), Among them, TUBA1A encodes a major neuronal α-tubulin that is highly expressed in the developing nervous system, and its de novo mutation disrupts brain development processes and is associated with severe brain malformations ( 12 ). These include lissencephaly, cerebellar hypoplasia, corpus callosum hypoplasia, and brainstem abnormalities ( 13 , 14 ).…”