Infant with Refractory Seizures and Characteristic Diffusion Restriction Pattern on Neuroimaging

A 13-month-old girl, the third born to consanguineous parents of South Asian origin, presented at 2 months of age with clustering of multiple brief episodes of focal seizures (eye-blinking, staring and desaturation) and generalized seizures.She was treated with supportive measures and multiple antiseizure medications.Antenatal ultrasound revealed intrauterine growth retardation (IUGR).The baby was born full term via vaginal delivery (birth weight, 2420 g); the baby required hospitalization due to poor sucking, hypotonia and hypoglycemia.Brain MRI at 9 weeks of age is shown (Figure 1A-H).Electroencephalography done at 2 months and 5 months of age showed multifocal epileptiform abnormalities, more frequent in the bilateral posterior head region and disorganized background.Screening for inborn error of metabolism was noncontributory.Subsequent trio genome sequencing 1 detected a homozygous pathogenic variant NM_033453.4:c.137del;p.(Gln46Argfs*43) in exon 3 of the inosine triphosphatase (ITPA) gene, confirming the diagnosis of developmental and epileptic encephalopathy 35 (DEE35).Both parents were heterozygous for this variant.There were no additional reportable genetic findings.The child exhibited failure to thrive, profound developmental delay, microcephaly and refractory seizures.Poor visual fixation and following of light were observed.Axial hypotonia was more pronounced than appendicular hypotonia, and brisk deep tendon reflexes were observed.Atrial septal defect (ASD), bilateral talipes equinovarus and congenital right hip dysplasia were also detected.Follow-up brain MRI at 9 months of age (Figure 2A-H) revealed persistence of diffusion restriction and a lag in myelination.Echocardiography follow-up at 7 months of age revealed moderate secundum ASD (left to right shunt), deficient aortic rim and moderately dilated right ventricle.ASD was likely to be fenestrated.Seizure control was achieved with a combination of levetiracetam, phenobarbitone and topiramate starting at 10 months of age.