Novel TUBB4A mutations and expansion of the neuroimaging phenotype of hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC)

Abstract

Hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) has recently been associated with a single heterozygous p.D249N mutation in TUBB4A. We describe two novel mutations in this gene. A p.C239F mutation was found in one of the originally described H-ABC patients, for whom we provide follow-up 11 years after the original publication. The second novel mutation, p.R262H, was found in a patient with a typical clinical presentation for H-ABC, but with a novel neuroimaging phenotype, given the absence of atrophy of the putamen and caudate nucleus despite 7 years of follow-up. The recent recognition of TUBB4A mutations as the underlying etiology of H-ABC will likely lead to the identification of subtler clinical and neuroimaging presentations of this disorder, like in our third patient. Thus mutations in this gene should be suspected in any patient with hypomyelination, regardless of the long-term presence of neostriatal atrophy.

Keywords: TUBB4A; hypomyelination with atrophy of the basal ganglia and cerebellum; tubulin beta 4.

FIG. 1.

A: Midsagittal T1- and (B) axial T2-weighted images of patient 1 at the age of 11 months show diffuse T2-hyperintense signal of the white matter, very small and T2-hyperintense caudate nuclei (arrows) and normal size of cerebellum, thalami and globi pallidi, while the putamina are completely atrophic and not visible. C: Midsagittal T1- and (D) axial T2-weighted follow-up images at the age of 9.8 years demonstrate atrophy of the cerebellum (arrows), unchanged diffuse T2-hyperintense signal of the white matter consistent with hypomyelination, decreased amount of white matter leading to cerebral atrophy and enlargement of the lateral ventricles, progressive atrophy of the head of the caudate nuclei (not visible anymore), mild reduction in size of the thalami, normal size of globi pallidi, and mild pontine atrophy (arrowhead). E: Midsagittal T1- and (F) axial T2-weighted images of Patient 2 at the age of 2.7 years reveal cerebellar atrophy superimposed on a small (hypoplastic) cerebellar vermis, mild atrophy of caudate nuclei (arrows) and putamina (arrowheads) that lack their normal intermediate signal intensity, and normal size of thalami and globi pallidi. G: Midsagittal T1- and (H) axial T2-weighted follow-up images at the age of 8.2 years show unchanged atrophy of the cerebellum and diffuse T2-hyperintense signal of the white matter consistent with hypomyelination, stable amount of white matter, progressive atrophy and loss of intermediate signal intensity of caudate nuclei (arrows) and putamina, subtle decrease in size of the thalami and normal size of globi pallidi. I: Midsagittal T1- and (J) axial T2-weighted images of patient 3 at age 2 years demonstrate diffuse T2-hyperintense signal of the cortical and subcortical white matter, T2-hypointense signal in the posterior limb of the internal capsule as well as genu and splenium of the corpus callosum, and normal signal intensity and size of thalami, normal signal intensity, but a rather globular appearance of the basal ganglia (arrows and arrowheads in J), and mild atrophy of the anterior vermis (arrow in I). K: Midsagittal T1- and (L) axial T2-weighted follow-up images at age 8.7 years reveal progressive cerebellar atrophy, unchanged signal intensity of the white matter consistent with hypomyelination, decreased amount of white matter with secondary cerebral atrophy and ventricular enlargement, and unchanged size and signal of basal ganglia (arrows and arrowheads) and thalami.

FIG. 2.

Multiple sequence alignment and Sanger sequencing of the two novel mutations. A: Multiple protein sequence alignment over the changed amino acids is shown from human to fish. B: Chromatogram of the novel p.C239F mutation. C: Chromatogram of the novel p.R262H mutation.