Gamma-Tubulin 1 (TUBG1) Mutation-Associated Lissencephaly and Microcephaly in an Indian Child: A Rare Case.

Malformations of cortical development (MCD) are a group of disorders affecting the normal development of the human cortex and are significant causes of delay in psychomotor development and epilepsy in children. Lissencephaly (smooth brain) forms a major group of brain malformations. Microtubules help in the migration of neuronal cells. Defect in tubulin gene alpha-tubulin (TUBA), beta-tubulin (TUBB), and gamma-tubulin (TUBG) leads to defective neuronal migration. This group of disorders is termed as "tubulinopathies." The important genes implicated in causing lissencephaly are LIS1, XLIS, and TUBA1A gene. Recently, a mutation in the TUBG1 gene is associated with it. Here, we report a one-and-a-half-year-old girl with global developmental delay, microcephaly, infantile-onset epilepsy, epileptic spasms, dysmorphism, and motor signs. There was no significant birth history. Neuroimaging (MRI) showed a broad thick gyri and a decreased number of sulci suggestive of lissencephaly/pachygyria spectrum. There was dilatation of the ventricles, and no grey matter heterotopia was noted. Sleep EEG showed multifocal epileptiform discharges. The child was treated with multiple anti-seizure medicines (ASMs). A genetic test, whole exome sequencing, was done to determine the etiology of MCD. A heterozygous missense variation in exon 6 of the TUBG1 gene was identified and reported as a "variant of unknown significance." Still, because the genotype matched with the clinical phenotype of the patient, it was considered clinically significant. Therefore, a complete diagnosis of TUBG1 mutation-associated cortical malformation (lissencephaly/pachygyria) with microcephaly and early-onset epilepsy was established. TUBG1 mutation is de novo in most cases, but parental testing is recommended. The parents of such patients need to be counseled about the need for prenatal testing and the risk of the disease to siblings. The overall prognosis in such cases is poor because of refractory seizures, physical limitations, and intellectual disability.