De Novo Mutations in POLG Presenting with Acute Liver Failure or Encephalopathy

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Historically, mitochondrial respiratory chain disorders have been recognized as a multisystemic disease with predominantly neuromuscular dysfunction (1). To date, most patients with mutations in POLG have presented with predominantly neurological features of headaches or focal seizures (2,3). In 1 study, end-state hepatic disease developed in only 2 of 26 cases (2). In another study, the only patients who experienced hepatic disease had been exposed to sodium valproate (3,4). Viral infection may be temporally associated with the development of acute liver failure in pediatric patients (5). However, the majority of children who contract viral infections do not experience liver failure. This suggests that there must be host factors that differentiate those children who do experience liver failure.CASE 1An infant girl was born at term with a normal birth weight to nonconsanguineous white parents. At 2 months of age she had feeding difficulties and hypotonia. Consequently, she underwent an extensive medical evaluation that included determination of plasma electrolytes, lactate/pyruvate, plasma amino acids, urine organic acids, chromosome karyotyping, fluorescence in situ hybridization for DiGeorge deletion, Angelman/Prader-Willi methylation studies, and magnetic resonance imaging (MRI) of the brain. The results of these tests were normal. Although the result of her initial newborn hearing screening was normal, subsequent testing showed her auditory brainstem response to be abnormal.At 4.5 months of age the patient contracted an influenza A infection. Concurrently she experienced hepatomegaly associated with severe hypoglycemia and elevations of plasma tyrosine (203 μmol/L, normal range [NR] 35–126), glutamine (994 μmol/L, NR 353–883), and alanine (1048 μmol/L, NR 152–459). Her serum lactate was increased to 9.8 mmol/L (NR <2.2). The markedly increased lactate-to-pyruvate ratio (43.9, NR <15) suggested a defect in the electron transport chain or tricarboxylic acid cycle (6).Abnormalities in liver synthetic function were demonstrated by an elevated prothrombin time of 23 seconds (NR 12.4–15.1) and a partial thromboplastin time of 58 seconds (NR 25–39). Her conjugated bilirubin increased to 1.89 mg/dL (NR 0.0–0.3), suggesting a cholestatic process. Conversely, there were only modest elevations in liver hepatocellular enzymes (aspartate aminotransferase [AST] 260 U/L, NR 16–46; alanine transaminase [ALT] 313 U/L, NR 29–46) without significant elevations in creatinine kinase. Ammonia was normal until the final stages of her illness, when it rose to 76 μmol/L (normal <50).Her neurological status did not show further decline. She did not experience seizures or nystagmus. However, a lumbar puncture 2 days after her second admission for worsening liver failure showed elevated cerebrospinal fluid (CSF) protein (550 mg/dL, NR 15–40) with a nearly acellular tap (13 white blood cells, 0 red blood cells). MRI of the brain showed nonspecific extraaxial fluid collection over the frontal cortex and also thickening and enhancement of the nerve roots of the cauda equina. These changes, sometimes seen in demyelinating polyneuropathies, suggested a possible neurodegenerative disorder.The results of other studies, including lysosomal enzymes, plasma very-long-chain fatty acids, and screening for common mutations of mitochondrial deoxyribonucleic acid (mtDNA) were normal. She showed signs of ongoing respiratory difficulty, pancreatitis, and renal tubulopathy. Despite aggressive medical therapy, the patient died at the age of 5.5 months.Liver biopsy revealed marked panlobular accumulation of neutral lipid within hepatocytes, with a predominantly microvesicular pattern (Fig. 1A). Moderate subacute portal inflammation, mild canalicular and hepatocellular cholestasis, and mild pseudoacinar formation were also noted. Glycogen staining was normal. Electron microscopy confirmed the microvesicular steatosis but did not demonstrate any structural abnormalities of mitochondria.

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