The importance of genetic testing in managing developmental epileptic encephalopathy in resource-limited settings: a...

Developmental epileptic encephalopathy (DEE) is a severe neurodevelopmental disorder characterized by developmental delay, regression, and intractable seizures. Genetic testing plays a crucial role in identifying underlying pathogenic variants, guiding treatment, and improving patient outcomes, particularly in resource-limited settings.

A one-and-a-half-year-old Sri Lankan boy was assessed due to global developmental regression. He exhibited motor delays, with developmental milestones around 9-12 months, including the ability to form a pincer grasp and stand with support. He showed regression in speech and swallowing. By 15 months, he could speak single words, which had reduced to monosyllable babbling by the time of presentation. He was born to healthy, non-consanguineous parents and had a healthy sibling. He had an uncomplicated antenatal and perinatal history and had no history of seizures. His paternal uncle also had developmental delay and epilepsy. He was found to have electrical status epilepticus in sleep (ESES) in the electroencephalogram (EEG) recording, and genetic testing revealed a CACNA₁E loss-of-function mutation. He had a variable response to antiseizure medications, with a good response to acetazolamide and significant functional deterioration with topiramate. He also responded to treatment for ESES.

Pathogenic variants of CACNA₁E, particularly those causing either gain-of-function or loss-of-function effects, are linked to severe neurodevelopmental disorders. Clinically, CACNA₁E mutations often present in early childhood with severe neurodevelopmental impairment, global developmental delay, autistic features, feeding difficulties, and self-injurious behaviors. The molecular mechanisms can explain the deterioration with topiramate and the improvement with acetazolamide, as the mutation causes a loss of function of the CACNA₁E gene, which is potentially exacerbated by the blocking of the same channel by topiramate and improved by acetazolamide. This case exemplified the use of genetic diagnosis for precision treatment. It highlighted the need to look for modifiable conditions such as epileptic encephalopathy in children with developmental delay and regression, even in the absence of seizures. The CACNA₁E mutation, EEG finding of ESES, and the responses to targeted treatment add to the literature of this rare disorder.