title: Abnormal hepatocellular mitochondria in methylmalonic acidemia.
abstract: Methylmalonic acidemia (MMA) is one of the most frequently encountered forms of branched-chain organic acidemias. Biochemical abnormalities seen in some MMA patients, such as lactic acidemia and increased tricarboxylic acid cycle intermediate excretion, suggest mitochondrial dysfunction. In order to investigate the possibility of mitochondrial involvement in MMA, we examined liver tissue for evidence of mitochondrial ultrastructural abnormalities. Five explanted livers obtained from MMA mut(0) patients undergoing liver transplantation were biopsied. All patients had previous episodes of metabolic acidosis, lactic acidemia, ketonuria, and hyperammonemia. All biopsies revealed a striking mitochondriopathy by electron microscopy. Mitochondria were markedly variable in size, shape, and conformation of cristae. The inner matrix appeared to be greatly expanded and the cristae were diminutive and disconnected. No crystalloid inclusions were noted. This series clearly documents extensive mitochondrial ultrastructure abnormalities in liver samples from MMA patients undergoing transplantation, providing pathological evidence for mitochondrial dysfunction in the pathophysiology of MMA mut(0). Considering the trend to abnormally large mitochondria, the metabolic effects of MMA may restrict mitochondrial fission or promote fusion. The correlation between mitochondrial dysfunction and morphological abnormalities in MMA may provide insights for better understanding and monitoring of optimized or novel therapeutic strategies.
authors.affiliation: Department of Pediatrics, Division of Medical Genetics, Lucile Packard Children's Hospital, Stanford University Medical Center , Palo Alto, CA , USA and.
authors.forename: Yael
authors.initials: Y
authors.lastname: Wilnai
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Enns
authors.forename: Anna-Kaisa
authors.initials: AK
authors.lastname: Niemi
authors.forename: John
authors.initials: J
authors.lastname: Higgins
authors.forename: Hannes
authors.initials: H
authors.lastname: Vogel
mesh_terms: D000592:Amino Acid Metabolism, Inborn Errors / Q000175:diagnosis / Q000378:metabolism* / Q000473:pathology; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D016031:Liver Transplantation; D008297:Male; D008854:Microscopy, Electron / Q000379:methods; D008928:Mitochondria / Q000378:metabolism / Q000648:ultrastructure*
keywords: Methylmalonic acidemia; electron microscopy; liver biopsy; mitochondria