Molecular syndromology · 2026
Acute Liver Failure following Valproate Exposure in a Teenager with Homozygous POLG c.2243G>C (p.Trp748Ser) Mutation: Late-Onset Presentation and Successful Liver Transplantation - A Case Report.
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Bingol Ibrahim, Umur Ozge, Sık Sare Guntulu, Yilmaz Tonguc Utku, Emiroglu Remzi, Citak Agop
Аннотация
INTRODUCTION: Valproic acid (VPA)-induced acute liver failure (ALF) is a severe and potentially fatal complication, particularly in pediatric patients with mitochondrial dysfunction. Mutations in the polymerase gamma (POLG) gene, especially those associated with Alpers-Huttenlocher syndrome, significantly increase susceptibility to VPA hepatotoxicity.
CASE PRESENTATION: We report a previously healthy 17-year-old girl who developed ALF after 1 month of VPA therapy prescribed for refractory focal seizures. Despite prompt discontinuation of VPA, she developed progressive jaundice, coagulopathy, hyperammonemia, and hepatic encephalopathy. Liver biopsy revealed microvesicular steatosis and centrilobular necrosis, consistent with drug-induced liver injury. Her condition deteriorated with hypertension, refractory seizures, and radiological features of posterior reversible encephalopathy syndrome (PRES). Whole-exome sequencing identified a NM_002693.3(POLG):c.2243G>C (p.Trp748Ser; p.W748S). Due to worsening hepatic function and neurological status, she underwent emergency orthotopic liver transplantation. Post-transplantation, liver function normalized, and seizures became intermittently controllable with levetiracetam and topiramate.
CONCLUSION: This case is notable for its late adolescent onset, homozygous POLG c.2243G>C (p.Trp748Ser) genotype, association with PRES, and successful emergency liver transplantation, thereby expanding the clinical spectrum of POLG-related VPA-ALF. These findings underscore the importance of POLG testing prior to VPA exposure in patients with suspected mitochondrial disease, even beyond early childhood.
CASE PRESENTATION: We report a previously healthy 17-year-old girl who developed ALF after 1 month of VPA therapy prescribed for refractory focal seizures. Despite prompt discontinuation of VPA, she developed progressive jaundice, coagulopathy, hyperammonemia, and hepatic encephalopathy. Liver biopsy revealed microvesicular steatosis and centrilobular necrosis, consistent with drug-induced liver injury. Her condition deteriorated with hypertension, refractory seizures, and radiological features of posterior reversible encephalopathy syndrome (PRES). Whole-exome sequencing identified a NM_002693.3(POLG):c.2243G>C (p.Trp748Ser; p.W748S). Due to worsening hepatic function and neurological status, she underwent emergency orthotopic liver transplantation. Post-transplantation, liver function normalized, and seizures became intermittently controllable with levetiracetam and topiramate.
CONCLUSION: This case is notable for its late adolescent onset, homozygous POLG c.2243G>C (p.Trp748Ser) genotype, association with PRES, and successful emergency liver transplantation, thereby expanding the clinical spectrum of POLG-related VPA-ALF. These findings underscore the importance of POLG testing prior to VPA exposure in patients with suspected mitochondrial disease, even beyond early childhood.