TUBB4A novel mutation reinforces the genotype–phenotype correlation of hypomyelination with atrophy of the basal ganglia and cerebellum

Sir, We read with great interest the article on rare leukoencephalopathy related to TUBB4A gene, hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC), which described 13 novel heterozygous mutations and the genotype-phenotype correlation (Hamilton et al., 2014). We analysed a cohort of patients with hypomyelination, defined by brain MRI, that were negative for PLP1 gene mutation, at the SARAH Network of Rehabilitation Hospitals in Brazil. We detected two unrelated H-ABC patients without the common c.745G4A/p.Asp249Asn mutation (Simons et al., 2013), which is described as the most frequent mutation. Our two patients fulfil the brain MRI image criteria for H-ABC (van der Knaap et al., 2002) presenting severe hypomyelination, small putamen with normal thalamus and globus pallidus, and cerebellar atrophy (Fig. 1). Genomic DNA was obtained from lymphocytes and TUBB4A gene was analysed by Sanger sequencing. One patient has the c.730G4A/p.Gly224Ser mutation described in three patients in Hamilton et al. (2014). The other patient had a novel heterozygous mutation in the C-terminal outer surface domain of tubulin ß4A monomer: c.1181T4G/p.Phe394Cys. The main clinical features of our patients are summarized in Table 1. The initial manifestation was the delay in developmental milestones at 4 months of age and both patients developed choreoathetosis and/or dystonia before the end of the second year of life. They did not acquire head control and both have only social awareness as maximum level of comprehension. To confirm the pathogenicity of the novel p.Phe394Cys missense mutation, web-based prediction programs were used. PolyPhen-2 predicted the p.Phe394Cys mutation as likely to be damaging. SIFT also predicted that this mutation affects protein function. MutPred considered it as a likely deleterious mutation. In both cases, there was no consanguinity and the family history was negative for other affected relatives. Parental DNA samples were available only from the parents of patient with p.Gly224Ser mutation and occurred de novo. Table 2 summarizes all articles published in the last 2 years describing mutation screening of the TUBB4A gene for hypomyelinating leukoencephalopathy (Simons et al., 2013; Blumkin et al., 2014; Ferreira et al., 2014; Hamilton et al., 2014; Miyatake et al., 2014; Purnell et al., 2014). In a recent study of eight Japanese patients (Miyatake et al., 2014), another three novel TUBB4A heterozygous mutations were reported that were not found in the Hamilton et al. (2014) multicentre study. Joining the patient of our group from a different Brazilian population, we consider that p.Gly224Ser is the second most frequent mutation in TUBB4A causing H-ABC. It is likely that new cases of known mutations and novel mutations in TUBB4A gene will soon be described. Regarding the clinical phenotype, our two patients were also more severely affected than patients with the common p.Asp249Asn mutation, supporting the genotype–phenotype correlation suggested by Hamilton et al. (2014). The description of doi:10.1093/brain/awu242 Brain 2014: Page 1 of 3 | e1