β-Tubulinopathy caused by a mutation of the TUBB2B gene: magnetic resonance imaging findings of the brain

Abstract

Patients with mutations in tubulin-related genes usually present with brain malformations, intellectual disability, epilepsy, microcephaly and ocular abnormalities. In these patients the diagnosis can be suggested by neuroimaging findings. We report a 5-year-old patient with characteristic magnetic resonance imaging findings including malformation of cortical development, fused basal ganglia, large head of the caudate nuclei, absent anterior limbs of the internal capsules, corpus callosum dysgenesis and dysplastic cerebellar vermis. Sequencing of the TUBB2B gene confirmed a heterozygous mutation: c. 260C>A (p. Pro87Gln).

Introduction

Microtubules are key to providing structural support and generating adequate force to allow appropriate cell migration during brain development.¹ They are made up of a single type of protein, tubulin, which consists of two polypeptides: α-tubulin, β-tubulin and γ-gamma tubulin,² which are encoded by related genes (TUBA1A, TUBA8, TUBB2A, TUBB4A, TUBB2B, TUBB3, TUBB).⁴

Tubulin-related diseases, also called ‘tubulinopathies’ are caused by mutations in one of the genes encoding different isoforms of tubulin, causing a wide and overlapping range of brain malformations.⁴ Clinical features often include intellectual disability, epilepsy (often refractory), microcephaly, and ocular abnormalities.⁵ In particular, the TUBB2B gene is located in chromosome 6p25.2, which codes for the β-tubulin isoform of tubulin.⁶

Historical and physical findings are non-specific, which is why magnetic resonance imaging (MRI) can demonstrate characteristic findings in tubulinopathies: such as lissencephaly, corpus callosum abnormalities, hypoplasia or dysplasia of the brain stem and dysplastic basal ganglia.⁷ However, genetic testing must be acquired for a definite diagnosis. To exemplify this, we report a patient with characteristic tubulinopathy findings on MRI in which a novel TUBB2B mutation was confirmed.

Case report

Our patient was delivered at 38 weeks’ gestation by caesarean section due to prenatal diagnosis of ventriculomegaly. He was the first-born child of non-consanguineous parents and had no family history of genetic disorders. He was initially evaluated at 19 months due to neurodevelopmental delays consisting of poor visual fixation and follow, poor social interaction, and stereotypies. At age 2 years, he began having generalized sleep-related tonic seizures. On physical examination, microcephaly, plagiocephaly, slight hypotonia and divergent strabismus were noted.

Initial genetic analysis was performed with karyotype and chromosomal microarray, both with normal results. At the same time, 3-Tesla MRI of the brain was obtained including standard three-dimensional gradient echo T1 and T2-turbo spin echo images (Figure 1), which showed an abnormal opercular gyral pattern, associated with fused basal ganglia, large head of the caudate nucleus and anterior limb of the internal capsule absence. Corpus callosum dysgenesis, dysplastic inferior cerebellar vermis and small pons were also evident. These findings are compatible with tubulin-related gene mutations, which prompted sequencing of tubulin encoding genes.

Figure 1.

(a) Axial T2-weighted image shows fused basal ganglia (white asterisk), large head of the caudate nuclei (arrow) and absence of anterior limbs of the internal capsules which are characteristic findings in tubulin mutations. An abnormal opercular-insular gyral pattern is seen (circle). The ventricles are enlarged, especially the posterior aspects of the lateral ventricles (arrowheads). (b) Sagittal T1-weighted image shows a thin corpus callosum (curved arrow) and a dysplastic inferior cerebellar vermis (double arrows). The brainstem, especially the pons (black asterisk), is small.

Sequencing of the TUBB2B gene confirmed a heterozygous mutation: c. 260C>A (p. Pro87Gln), which was absent in both parents. The patient is currently 5 years old; his seizures are controlled with valproic acid and levetiracetam. However, stereotypies and severe language delay persist.

Discussion

There are different phenotypes that can be seen in patients with tubulin gene mutations. Initially, tubulin gene mutations were thought of as causing lissencephaly or polymicrogyria.⁸ However, patients with tubulinopathies can display a wide spectrum of morphological abnormalities, in which overlapping phenotypical malformations can occur between the mutations of the different tubulin genes, including: (a) severe lissencephaly with cerebellar and brainstem hypoplasia in which the TUB1A1 gene has been found in 30% of patients; (b) moderate lissencephaly with cerebellar hypoplasia with pachygyria, corpus callosum defects, and moderate hypoplasia of the brainstem and cerebellum; (c) classic lissencephaly; and (d) polymicrogyria, corpus callosum abnormalities, brainstem and cerebellum hypoplasia;⁶ this last one matching the findings in our patient.

In 2012, Guerrini et al. reported a case series of three patients with TUBB2B mutations, in which two of the patients exhibited polymicrogyria, one of them showed a small pons and one of them a thin corpus callosum. However, cerebellum morphology was normal in three of them,⁹ in contrast with our patient in whom dysplastic inferior cerebellar vermis was noted and was also associated with fused basal ganglia and absence of the anterior limb of the internal capsule. This case emphasises the heterogeneity of possible brain malformations associated with tubulin-related gene mutations, in this case, gene TUBB2B. Nonetheless, knowledge of specific MRI findings in the tubulin-related gene mutation spectrum can be helpful to assist a diagnosis and lead to suitable genetic testing.

Conclusion

In patients with epilepsy and neurodevelopmental delays in which MRI findings include polymicrogyria, fused basal ganglia, large head of the caudate nucleus, anterior limb of the internal capsule absence, corpus callosum dysgenesis, dysplastic inferior cerebellar vermis and/or small pons should prompt a search for TUBB2B mutations and/or other tubulin-related spectrum mutations.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Conflict of interest

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.