Hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) is caused by heterozygous variants in TUBB4A1,2. Variants in TUBB4A are known to cause two different clinical conditions: dystonia type 4 (DYT4) and H-ABC1,3. The DYT4 phenotype is characterized by whispering dysphonia, generalized dystonia, and gait ataxia. Magnetic resonance imaging (MRI) typically reveals a normal brain findings3. Patients with H-ABC exhibit clinical onset in early infancy, with developmental delay, extrapyramidal symptoms, progressive spastic tetraplegia, ataxia, dysarthria, cognitive and sensory deficits, and seizures1. Characteristic MRI findings include white matter hypomyelination, the absence or disappearance of the putamen, and cerebellar atrophy1.

There is great diversity in the age of onset, clinical course, and brain MRI findings associated with TUBB4A variants4,5. In particular, there are a series of TUBB4A-associated phenotypes with isolated hypomyelination that do not fit either DYT or H-ABC patterns4,5,6,7,8,9,10,11,12,13,14,15,16,17,18.

We describe the case of a patient with TUBB4A-related hypomyelination caused by a c.1088T > C, p.(Met363Thr) variant. This variant has been reported once previously, but no details of the course of the disorder were available19. The following report presents the case of this patient with TUBB4A-related hypomyelination and cerebellar atrophy without atrophy of the basal ganglia.

The patient was an 11-year-old boy who presented with a neurodevelopmental disorder. His family and perinatal histories were unremarkable. He first spoke at 12 months of age and began walking independently at 18 months of age. From 3 years of age, he was noted to be clumsy and unsteady and exhibited difficulties with comprehension. He attended both special and regular education classes in elementary school. At the age of 10 years, he was diagnosed with mild intellectual disability (IQ = 52). Physical examination revealed no abnormalities. However, the neurological examination found brisk deep tendon reflexes, a bilateral Babinski sign, ankle clonus, upper limb dystonia, and abnormal tandem gait. MRI at the age of 8 years revealed cerebral 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).

Fig. 1: Brain MRI images.
figure 1

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.

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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 hypomyelination4,18. 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).

Table 1 Summary of previously reported TUBB4A variants of H-without AB.
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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 variants20. 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 matter3. There was a twofold difference between the cerebellum and thalamus, which had the lowest expression3. 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.