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A 4-year-old male child, born to non-consanguineous parents by caesarean section with an uneventful perinatal period, presented with seizures beginning at 4 months of age. Initial events were infantile spasms occurring 30 to 40 times per day, and subsequently also developed generalized tonic–clonic seizures. He had a profound global developmental delay, with a developmental quotient of less than 20. There was no significant family history. On examination, the child had facial dysmorphism and microcephaly without neurocutaneous stigmata. He had bilateral lower limb hypotonia and preserved deep tendon reflexes. EEG showed diffuse background slowing with continuous spike-and-wave discharges over bilateral posterior head regions. Other investigations, including hemogram, renal and liver function tests, serum electrolytes, and metabolic screening, were within normal limits. MRI of brain revealed markedly thickened cerebral cortex with paucity of sulcation, dilatation of the lateral ventricles with smooth ventricular margins, and abnormal gray–white matter differentiation consistent with frontal pachygyria with posterior-predominant agyria. There was associated dysmorphic corpus callosum and cerebellar hypoplasia ([Figs. 1] and [2]). Genetic testing with whole exome sequencing (WES) identified a heterozygous missense variant c.1204C > T in exon 4 of TUBA1A gene that results in amino acid substitution p.Arg402Cys, which was classified as a likely pathogenic mutation. However, parental genetics could not be done due to financial constraints. The child was treated with a course of intravenous methylprednisolone (30 mg/kg/day), resulting in a reduction of spasms from 10–12 to approximately 3–4 episodes per day. Antiseizure medications were optimized with valproate, clobazam, and lamotrigine, along with supportive supplements. A plan for monthly pulse methylprednisolone therapy for three additional months was advised under medical supervision.

Fig. 1 (A) Axial and (B) sagittal T1 MRI of brain. Markedly thickened cerebral cortex (white arrow) with paucity of sulcation, dilatation of the lateral ventricles (blue arrow) with smooth ventricular margins, and abnormal gray–white matter differentiation (black arrow).Fig. 2 Parasagittal (T1 image) and posterior fossa section (T2 image). (A) Parasagittal T1-weighted image demonstrates a dysmorphic corpus callosum characterized by small rostrum and genu with flattening of the anterior body (blue arrow). The posterior callosal segment appears relatively preserved. Associated mild vermian hypoplasia is also noted. (B) Axial T2-weighted image at the level of the posterior fossa shows smooth cerebellar hemispheres (gray arrow) with reduced foliation and mildly hypoplastic vermis.

Lissencephaly is a rare congenital malformation caused by defective neuronal migration during early gestation.[1] Clinically, it presents with severe developmental delay, hypotonia, and feeding difficulties. In the first 2 years of life, more than 90% of children with lissencephaly present with seizures, mostly infantile spasms.[2] Among the genetic causes, TUBA1A mutations are relatively rare and often associated with complex cortical dysgenesis, early refractory seizures, and profound neurodevelopmental impairment. TUBA1A-related lissencephaly is a distinct subgroup of neuronal migration disorders characterized by disruption of microtubule-dependent cortical development. The TUBA1A gene encodes α-tubulin, a critical component of microtubules which is essential for neuronal proliferation, migration, and axonal guidance. Pathogenic variants interfere with microtubule functioning and molecular interactions, resulting in abnormal cortical lamination and a broad spectrum of brain malformations.[3] Recent large cohort studies have demonstrated that TUBA1A mutations account for approximately 1 to 7% of unexplained classic lissencephaly and nearly one-third of lissencephaly with cerebellar hypoplasia, thus establishing TUBA1A as a major contributor to severe cortical malformations.[4] Based on neuroimaging patterns and mutation location, affected individuals are classified into distinct phenotypic groups.[5] Group 1 and group 2 patients, who typically harbor recurrent mutations at residue R402 (p.R402C or p.R402H), exhibit imaging patterns nearly indistinguishable from those of LIS1-associated classical lissencephaly. These patients demonstrate frontal pachygyria with posterior-predominant agyria (classic LIS grades 2–3), a dysmorphic corpus callosum with a small rostrum and genu, flattened anterior body, poorly myelinated internal capsules, and rounded hippocampi with thickened leaves. Mild cerebellar vermian hypoplasia and tectal enlargement are additional distinguishing features compared with LIS1-related disease. In group 2, the phenotype may progress to near-complete agyria, closely mimicking Miller–Dieker syndrome.[6]

In contrast, non-R402 mutations (groups 3 and 4) are associated with more heterogeneous and severe phenotypes, including diffuse pachygyria, chaotic anterior–posterior gradients, complete or partial agenesis of the corpus callosum, marked cerebellar hypoplasia, and brainstem abnormalities, collectively classified as lissencephaly with cerebellar hypoplasia.[5]

Our patient demonstrated imaging features consistent with the group 1 TUBA1A phenotype, including posterior-predominant agyria-pachygyria, ventriculomegaly, dysmorphic corpus callosum, and cerebellar vermian hypoplasia. This pattern closely resembles LIS1-associated classical lissencephaly and is consistent with previously described p.R402-associated TUBA1A cases. The radiological similarity to Miller–Dieker syndrome highlights the importance of molecular testing, as TUBA1A mutations can be phenotypically similar to LIS1-related disease despite the absence of chromosome 17p13.3 deletions. Clinically, affected children present with early-onset epileptic encephalopathy, severe global developmental delay, hypotonia, visual impairment, and feeding difficulties. Infantile spasms are common and often refractory. Our patient exhibited infantile spasms with profound developmental delay, showing a partial response to pulse corticosteroid therapy. Given the cost and availability issues related to ACTH, we selected this approach over oral steroids as a practical and reliable alternative to ACTH, based on our institutional experience demonstrating the safety and efficacy of intravenous methylprednisolone in epileptic encephalopathy.[7] [8]

Currently, management remains supportive, focusing on seizure control and multidisciplinary rehabilitation. Prognosis is guarded, with most children remaining severely developmentally impaired. Early recognition of characteristic MRI patterns and timely genetic confirmation are essential for accurate diagnosis, prognostication, and genetic counseling. TUBA1A sequencing should be strongly considered in children with classical lissencephaly, particularly when cerebellar abnormalities or LIS1-negative phenotypes are encountered.

Article published online:
06 May 2026

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