Abstracts

Rationale: Mutations in the α-1a Tubulin (TUBA1A) gene have recently been described in patients with malformations of cortical development ranging from perisylvian to posteriorly predominant pachygyria with associated malformations of the corpus callosum and cerebellum. Methods: MRI of the brain, EEG, cardiac and renal ultrasound, and X-ray of the spine were carried out. MLPA analysis of LIS1, DCX, POMT1, POMGnT1, FLNA genes as well as sequencing of DCX and TUBA1A genes were performed. Results: The proband, a 18-month old boy, was born at term after an uneventful pregnancy. Head circumference at birth was 31 cm. He presented with severe hypotonia and feeding difficulties, and developed neonatal convulsions for which treatment with phenobarbital, phenytoin and valproate was initiated. Early EEGs showed episodes of high voltage delta activity with diffuse irregular spikes, followed by episodes of low voltage activity with very little variation. Seizures eventually were controlled by vigabatrin, topiramate and phenobarbital. MRI of the brain showed frontoparietal agyria and less severe pachygyria over the occipital and temporal lobes. The anterior limb of the internal capsule was small, the corpus callosum was thin and there was severe ventriculomegaly. The sylvian fissure was verticalised. There was mild hypoplasia of the inferior vermis and the medio-inferior aspect of the cerebellar lobes. Cardiac and renal ultrasounds were normal. X-ray of the spine showed a spina bifida occulta at S2. MLPA analysis revealed no duplicaton or deletion in the above mentioned genes. Mutation analysis of TUBA1A showed that the patient was heterozygous for a novel missense mutation c.629A>G (p.Tyr210Cys). The mutation was absent in both parents. Conclusions: Patients with lissencephaly often present with neonatal seizures. Mutation analysis of TUBA1A is indicated in patients with lissencephaly, especially in the presence of microcephaly and associated malformations including dysgenesis of the anterior limb of the interal capsule, thin corpus callosum, and inferior vermis hypoplasia.