Tubulinopathies continued: refining the phenotypic spectrum associated with variants in TUBG1

Abstract

Tubulinopathies are a heterogeneous group of conditions with a wide spectrum of clinical severity resulting from variants in genes of the tubulin superfamily. Variants in TUBG1 have been described in three patients with posterior predominant pachygyria and microcephaly. We here report eight additional patients with four novel heterozygous variants in TUBG1 identified by next-generation sequencing (NGS) analysis. All had severe motor and cognitive impairment and all except one developed seizures in early life. The core imaging features included a pachygyric cortex with posterior to anterior gradient, enlarged lateral ventricles most pronounced over the posterior horns, and variable degrees of reduced white matter volume. Basal ganglia, corpus callosum, brainstem, and cerebellum were often normal, in contrast to patients with variants in other tubulin genes where these structures are frequently malformed. The imaging phenotype associated with variants in TUBG1 is therefore more in line with the phenotype resulting from variants in LIS1 (a.k.a. PAFAH1B1). This difference may, at least in part, be explained by gamma-tubulin's physiological function in microtubule nucleation, which differs from that of alpha and beta-tubulin.

Fig. 1

Imaging characteristics patients 1–4 and a normal subject. Brain MRI of patient 1 at age 36 years. Sagittal planes through the midline (a) show a normal corpus callosum, brainstem, and cerebellum. Axial T1-weighed images (b) and T2-weighed images (c) show pachygyria with a posterior to anterior gradient, enlarged posterior horns of the lateral ventricles, and enlarged perivascular spaces. Brain MRI of patient 2 at age 11 years. Sagittal planes (d) show a thin corpus callosum, hypoplasia of the brainstem, and the cerebellar vermis. Axial T2-weighed images (e, f) show diffuse lissencephaly, reduced white matter, and enlarged lateral ventricles and dysplastic basal ganglia. Brain MRI of patient 3 at age 1 year 6 months (g, h) and patient 4 at age 12 months (i, j, k). Sagittal planes (g, i) show a normal appearance of corpus callosum, brainstem, and the cerebellum. Axial T1-weighed images (h, j, k) show pachygyria with a posterior to anterior gradient, enlarged lateral ventricles, and reduced white matter. Brain MRI of a healthy subject (age 4 years). Sagittal image (l). Axial T2-weighed images (m, n)

Fig. 2

Imaging characteristics patients 5–8. Brain MRI of patient 5 at age 13 years. Sagittal planes through the midline (a) show the absence of malformations of the corpus callosum, brainstem, and cerebellum. Axial T1-weighed images (b) and T2-weighed images (c) show pachygyria with a posterior to anterior gradient and enlarged posterior horns of the lateral ventricles. Brain MRI of patient 6 at age 2 months. Sagittal planes (d) show a thin corpus callosum, absence of hypoplasia of the brainstem, or the cerebellar vermis. Axial T2-weighed images (e, f) show diffuse pachygyria with a posterior to anterior gradient and enlarged lateral ventricles. Brain MRI of patient 7 at age 1 year 6 years. Sagittal images (g) show a normal appearance of corpus callosum, brainstem, and the cerebellum. Axial T2-weighed images (h, i) show pachygyria with a posterior to anterior gradient with almost normal frontal lobes, enlarged posterior horns of the lateral ventricles, and reduced white matter. Brain MRI of patient 8 at age 9 years. Sagittal images (j) show hypoplasia of the corpus callosum. Axial T2-weighed images (k, l) show pachygyria with a posterior to anterior gradient and important involvement of the temporal lobes, bilateral parietal infoldings, dysplastic basal ganglia, enlarged lateral ventricles, and reduced white matter

Fig. 3

Distribution of the variants in the TUBG1 gene. Linear (a) and 3D (b) representation of the TUBG1 gene showing its functional domains and the distribution of the described TUBG1 variants. The variant in red in a represents the recurrent variant detected in four patients. The 3D structure is based on PDB ID: 3CB2 (crystal structure of gamma-tubulin bound to GDP) using NGL viewer [38, 39]