To present two phenotypically distinct cases of adenylosuccinate lyase (ADSL) deficiency sharing the same genetic mutation, highlighting diagnostic and therapeutic challenges.

A 2-month-old boy born via uncomplicated caesarean delivery presented with a history of infantile spasms. MRI brain showed periventricular leukomalacia. High-dose steroids, levetiracetam, clobazam and ACTH therapy were started. Genetic analysis revealed a homozygous R426H mutation in the ADSL gene. The child was evaluated for breakthrough seizures, insomnia, inability to walk and manic episodes at age 7. He underwent trials of risperidone, medical marijuana and quetiapine, with limited benefit. Seizure control, irritability and sleep improved on brivaracetam at age 12.

The boy’s older sister, born via uncomplicated term vaginal delivery, presented with a history of seizures and skull fracture soon after birth. MRI brain showed possible leukodystrophy. Genetic testing done following her brother’s diagnosis revealed the same R426H mutation. Cortical visual impairment and electroencephalographic features of intractable multifocal epilepsy were noted. Seizure activity worsened prior to menarche at age 10; cannabidiol and gabapentin produced minimal improvement. Electromyography in view of decreased hip movement showed possible severe right lower lumbosacral plexopathy. Weight bearing gradually improved with orthoses. The child received a vagus nerve stimulator implant, which improved seizure control. Breakthrough seizures continued to occur prior to menses, and birth control was initiated. At age 15, she is on clobazam and medical marijuana, which have decreased seizure frequency.