A TUBB4A Met363Thr variant in pediatric hypomyelination without atrophy of the basal ganglia

TUBB4A gene variants cause dystonia type 4 and hypomyelination with atrophy of the basal ganglia and cerebellum. We report the case of a child with delayed motor development, intellectual disability, and dystonia. Magnetic resonance imaging revealed hypomyelination and progressive cerebellar atrophy without atrophy of the basal ganglia. Whole-exome sequencing revealed a de novo heterozygous variant, c.1088T > C, p.(Met363Thr), in TUBB4A. The present case further supports the vulnerability of the cerebellum in patients with TUBB4A pathogenic variants.

white matter hypomyelination but no atrophic findings in the basal ganglia or cerebellum (Fig. 1A). MRI at the age of 11 years revealed hypomyelination and atrophy of the cerebellum, but the basal ganglia size was normal (Fig. 1B, C). Whole-exome sequencing was performed, and the NM_006087.4: c.1088T > C, p.(Met363Thr) variant was detected. Since neither parent had this variant, it was considered a de novo variant. This variant was absent in gnomAD v3.1.2 (accessed January 2022), the ToMMo 14KJPN Allele Frequency Panel (v v20211208) (https://jmorp. megabank.tohoku.ac.jp/202112/), and 218 in-house Japanese exome control datasets. In silico evaluation tools predicted this variant to be deleterious (PROVEAN −3.42, CADD v1.6 phred 23.8, M-CAP 0.869). Based on the American College of Medical Genetics and Genomics standards and guidelines, the c.1088T > C variant was classified as likely pathogenic (PS2, PM2, PP3).
TUBB4A variants causing H-ABC were first reported in 2013, with an onset age between 2 months and 4.5 years (median age: 6 months) 8 . The frequency of atrophy of the basal ganglia in H-ABC has been reported to be 70% in the capsule and 30% in the caudate nucleus within 2 years of onset but progresses to 97% and 53% (2-12 years after onset) and then 100% and 90%, respectively, (>12 years after onset) 20 . However, some patients with hypomyelination but without atrophy of the basal ganglia have been reported to have isolated hypomyelination 4,18 . We summarize the variants of TUBB4A-related hypomyelination without atrophy of the basal ganglia (H-without AB) in Table 1. The age at onset of clinical symptoms was between 1 month and 33 years (median age: 15 months), which is later than that for H-ABC. Including the present case, cerebellar atrophy was reported with 12 of the 17 variants (70%) ( Table 1).
Several correlations between genotype and phenotypic severity in H-ABC have been suggested. Patients with the common c.745G > A variant have a more benign phenotype than patients with other variants 20 . Lu et al. 8 reported that variants located on the outside of the αβ-tubulin heterodimer, distant from the guanosine triphosphate domain, are likely to result in milder phenotypes without atrophy of the basal ganglia or cerebellum. For the c.900G > T, c.1064A > T, and c.1172G > A variants, there have been two reports of phenotypes characterized by hypomyelination without atrophy of the basal ganglia (Table 1). However, Tonduti et al. 10 reported that patients with the same variant showed different disease courses.
To our knowledge, there has been no report on TUBB4A-related hypomyelination with only atrophy of the basal ganglia. Therefore, we speculate that the cerebellum is more vulnerable than the basal ganglia. The highest expression of TUBB4A was in the cerebellum, followed by the putamen and white matter 3 . There was a twofold difference between the cerebellum and thalamus, which had the lowest expression 3 . The different TUBB4A expression levels in different brain regions may explain this distinct vulnerability.

HGV DATABASE
The relevant data from this Data Report are hosted at the Human Genome Variation Database at https://doi.org/10.6084/m9. figshare.hgv.3199. Fig. 1 Brain MRI images. A Axial T2 image at the age of 8 years shows diffuse hypomyelination without atrophy of the basal ganglia. B Axial T2 image at the age of 11 years shows persistent hypomyelination without atrophy of the basal ganglia. C Sagittal T1 image at the age of 11 years shows atrophy of the cerebellum.