Polymicrogyria with Epilepsy and Macrocephaly: A Unique Genetic Cause

A 21-month-old girl, born at term to nonconsanguineous parents, presented with global developmental delay and large head along with focal-onset epilepsy for the past 3 months. She had attained social smile at 3 months, head control at 5 months, and was able to sit with support by 10 months; however, she had not achieved independent walking or meaningful speech. At 18 months of age, the child developed focal-onset seizures characterized by abrupt behavioral arrest followed by rhythmic clonic movements involving the right side of the face and upper limb. The events were occasionally accompanied by sustained eye deviation to the right, drooling, and transient apnea, without cyanosis. Each episode lasted approximately 30 to 60 seconds, followed by brief postictal drowsiness. There was no history suggestive of epileptic spasms. Seizures were controlled on levetiracetam at 40 mg/kg/day and sodium valproate at 35 mg/kg/day. Family history was not contributory. Examination showed a large head with dolichocephaly (head circumference 49.8 cm, > +3 standard deviation [SD] as per the World Health Organization growth standards), prominent scalp veins and forehead, large fibrous anterior fontanelle, small midface, and prominent columella ([Fig. 1A, B]), central hypotonia, normal fundi, and absence of polydactyly. Electroencephalogram was abnormal, revealing diffuse 3 to 4 Hz activity and occasional sharp and slow wave discharges from the left hemisphere, which were accentuated in sleep. Magnetic resonance imaging of the brain showed bilateral perisylvian polymicrogyria ([Fig. 1C–F]). Exome sequencing identified a heterozygous missense variant c.1393C>T (p.Arg465Trp) in exon 14 of AKT3. This is consistent with autosomal-dominant AKT3-related Megalencephaly-Polymicrogyria-Polydactyly-Hydrocephalus Syndrome (MPPH-2). The variant was absent in both parents, supporting a de novo occurrence. The variant has been reported in multiple individuals with AKT3-related disorders.[1]

Fig. 1 (A–F) Clinical photograph of the case showing (A) large head with facial dysmorphism, increased intercanthal distance, prominent forehead, small midface, thin upper lip, long philtrum, prominent columella, and (B) dolichocephaly. (C–F) Axial brain magnetic resonance imaging (MRI) demonstrates bilateral perisylvian and frontoparietal polymicrogyria. (C, E) T2-weighted images reveal irregular cortical thickening, abnormal gyral pattern, and shallow sulci along the perisylvian cortex and posterior frontal–parietal regions bilaterally, with poor gray–white matter differentiation. (D, F) Corresponding T1-weighted images show undulating cortical margins and thickened cortex (arrows) confirming polymicrogyria. Mild ventriculomegaly and reduced white matter volume are also noted, consistent with mild hydrocephalus. The basal ganglia, thalami, brainstem, and cerebellum appear normal.

MPPH2 (MIM# 615937) is a rare, autosomal-dominant, developmental brain overgrowth syndrome characterized by megalencephaly and underlying polymicrogyria causing macrocephaly with or without hydrocephalus, described first by Mirzaa et al in 2004.[2] The AKT3 gene encodes a serine/threonine kinase important in cell growth, brain development, and synaptic plasticity.

The brain overgrowth is an essential component and persists even after correction of hydrocephalus. The brain malformations may include hemimegalencephaly, polymicrogyria, cerebellar tonsillar ectopia, or a thick corpus callosum. Postnatal head growth ranges from normal to 10 SD above the mean. Epilepsy is often focal-onset, and infantile spasms have also been seen.[3] [4] In children presenting with epilepsy and macrocephaly, particularly when associated with polymicrogyria, consideration of MPPH syndromes is warranted. Early genetic testing not only establishes the diagnosis by identification of pathogenic variants in one of the three genes: PIK3R2 (MPPH1 syndrome), AKT3 (MPPH2 syndrome), and CCND2 (MPPH3 syndrome) but also facilitates counseling and prognostication.

Conflict of Interest

None declared.

Authors' Contributions

Conception and design: K.P., A.G.S.

Acquisition of data: K.P., S.S., S.V., S.V.

Analysis and interpretation of data: S.V., A.G.S.

Drafting the manuscript: K.P., S.S., S.V., A.G.S.

Revising it for intellectual content: S.V., A.G.S.

Final approval of the completed manuscript: A.G.S.

• References

• 1 Lin L, Zhang Y, Pan H, Wang J, Qi Y, Ma Y. Clinical and genetic characteristics and prenatal diagnosis of patients presented GDD/ID with rare monogenic causes. Orphanet J Rare Dis 2020; 15 (01) 317
• 2 Mirzaa G, Dodge NN, Glass I. et al. Megalencephaly and perisylvian polymicrogyria with postaxial polydactyly and hydrocephalus: a rare brain malformation syndrome associated with mental retardation and seizures. Neuropediatrics 2004; 35 (06) 353-359
• 3 Epilepsy Phenome/Genome Project, Epi4K Consortium. Diverse genetic causes of polymicrogyria with epilepsy. Epilepsia 2021; 62 (04) 973-983
• 4 Rivière JB, Mirzaa GM, O'Roak BJ. et al; Finding of Rare Disease Genes (FORGE) Canada Consortium. De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes. Nat Genet 2012; 44 (08) 934-940

Publication History

Article published online:
20 January 2026