CAD mutations and uridine-responsive epileptic encephalopathy

Area of Science:

• Biochemistry
• Genetics
• Neurology

Background:

• Unexplained global developmental delay and epilepsy in childhood represent a significant socioeconomic challenge.
• Effective treatments for rare neurometabolic disorders are often lacking, despite advances in molecular diagnostics.
• Inborn errors of metabolism treatable by dietary intervention are notable exceptions.

Purpose of the Study:

• To identify the genetic cause of a severe neurometabolic disorder characterized by global developmental delay, epileptic encephalopathy, and anemia.
• To investigate the therapeutic potential of uridine supplementation in patients with identified genetic defects.

Main Methods:

• Exome sequencing was performed on three families with affected children.
• Genetic variants were identified and correlated with clinical phenotypes.
• The efficacy of oral uridine supplementation was assessed in surviving patients.

Main Results:

• Biallelic mutations in the CAD gene were identified in four children presenting with global developmental delay, epileptic encephalopathy, and dyserythropoietic anemia.
• Two affected children experienced a fatal neurodegenerative course.
• Uridine supplementation led to immediate seizure cessation and significant developmental improvements in the surviving children, with normalization of blood smears and resolution of anemia.

Conclusions:

• CAD deficiency is a treatable neurometabolic disorder characterized by global developmental delay, anemia, and seizures.
• Uridine supplementation represents a highly effective treatment, significantly improving neurological and hematological parameters.
• CAD deficiency is a potential candidate for inclusion in future newborn screening programs due to its treatable nature.