Novel c.221+1dup pathogenic variant in AGK gene linked to Sengers syndrome

Abstract

Sengers Syndrome (SS) is a rare autosomal recessive mitochondrial disorder caused by mutations in the acylglycerol kinase (AGK) gene on chromosome 7, also known as cardiomyopathic mitochondrial DNA depletion syndrome (MTDPS10). This disorder disrupts mitochondrial DNA function and energy metabolism, presenting with symptoms such as congenital cataracts, hypertrophic cardiomyopathy, skeletal myopathy, exercise intolerance, and lactic acidosis. Previous research has shown SS affects oxidative phosphorylation and mitochondrial respiration, implicating the TIM22 complex and carrier import. We report a 32-year-old Palestinian female with a novel homozygous pathogenic variant, c.221+1dup, in the AGK gene. Her clinical presentation included chronic lactic acidosis, congenital cataracts, exercise intolerance, mild hypertrophic cardiomyopathy, and persistent muscle fatigue. Genetic testing was essential for confirming the diagnosis of Sengers Syndrome, revealing this previously undocumented variant. Family history indicated a hereditary pattern with a brother exhibiting similar symptoms. Typically diagnosed in infancy, SS's diverse and rare clinical manifestations can sometimes delay diagnosis. This case emphasizes the importance of considering SS in differential diagnoses when patients present with ocular lesions, lactic acidosis, muscle weakness, and cardiomyopathy. The novel AGK gene variant, with its rarity, highlights the need for heightened clinical suspicion and genetic evaluation, while suggesting further investigation into its pathogenic role and potential founder effects to enhance understanding of the genetic diversity of Sengers Syndrome.