Mitochondrial T9098C sequence change in the MTATP6 gene and development of severe mitochondrial disease after in utero antiretroviral prophylaxis.

Mitochondrial toxicity is a well-recognized adverse effect of nucleoside reverse transcriptase inhibitor therapy for human immunodeficiency virus (HIV) infection. Transient lactic acidosis is often observed in children born after in utero antiretroviral prophylaxis against mother-to-child transmission of HIV. However, the extent and the mechanism of in utero adverse effects are largely unknown. We describe a 4-year-old girl who presented with manifestations of severe mitochondrial disease, specifically, developmental and growth delay, hypotonia, lactic acidosis, congenital cataracts, and pancreatitis. Her HIV-positive mother was receiving lamivudine, zidovudine, and nelfinavir mesylate during her pregnancy. The child tested HIV negative after birth. She was found to have a homoplastic T9098C sequence change in the mitochondrial gene coding for adenosine 5'-triphosphate synthase 6 (MTATP6) that was previously reported as a mitochondrial polymorphism. This polymorphism is in the MTATP6 gene-coding sequence and leads to the replacement of a nonpolar amino acid with a polar amino acid. Because of the typical clinical manifestations of mitochondrial disorder and because of the nature of the mitochondrial sequence change, the observed polymorphism likely predisposed this patient to develop severe antiretroviral-associated mitochondrial disease. Mitochondrial sequence alterations may be important factors in mitochondrial toxicity associated with antiretroviral treatment. Mitochondrial sequencing may be warranted in cases of persistent lactic acidosis after antiretroviral prophylaxis to further study this association.