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.

Keywords: TUBA1A; TUBB2B; developmental and epileptic encephalopathy; pediatric; tubulinopathy.

Figure 1

Sleep EEG of Case 1. It showed asymmetric slow background activities with focal discharges (arrows) from the left frontotemporal region.

Figure 2

Brain MRI (T1WI) of Case 1 showed marked dilated ventricles with displaced cerebellum (A), dysgenesis of corpus callo-sum, pachy/polymicrogyria (white arrows in (B–D)) and small vermis (arrowhead in (D)).

Figure 3

Sanger sequencing confirmed TUBB2B de novo mutation (NM_178012.5:c.629T>A; p.Ile210Asn) of Case 1 identified by whole exome sequencing (WES).

Figure 4

Sleep EEG of Case 2. It showed bilateral focal discharges (arrows) from central and temporal regions.

Figure 5

Brain MRI of Case 2 showed lissencephaly (white arrows), mildly dilated posterior horns of ventricles with dysgenesis of carpus callosum, and small vermis (arrow) ((A–C): T1WI, (D): T2WI).

Figure 6

Sanger sequencing confirmed TUBA1A de novo mutation (NM_006009.4: c.629A>G; p.Tyr210Cys) of Case 2 identified by whole exome sequencing (WES).