Deoxyguanosine kinase deficiency presenting as neonatal hemochromatosis. Mol Genet Metab

Department of Human and Molecular Genetics, Baylor College of Medicine, Houston, TX, USA.
Molecular Genetics and Metabolism (Impact Factor: 2.63). 07/2011; 103(3):262-7. DOI: 10.1016/j.ymgme.2011.03.006
Source: PubMed


Mutations in DGUOK result in mitochondrial DNA (mtDNA) depletion and may present as neonatal liver failure. Neonatal hemochromatosis (NH(1)) is a liver disorder of uncertain and varied etiology characterized by hepatic and non-reticuloendothelial siderosis. To date, deoxyguanosine kinase (dGK(2)) deficiency has not been formally recognized in cases of NH. We report an African American female neonate with clinical and autopsy findings consistent with NH, and mtDNA depletion due to a homozygous mutation in DGUOK. This report highlights hepatocerebral mtDNA depletion in the differential of neonatal tyrosinemia, advocates considering dGK deficiency in cases of NH, and posits mitochondrial oxidative processes in the pathogenesis of NH.

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    ABSTRACT: This paper reports studies of two patients proven by a variety of studies to have mitochondrial depletion syndromes due to mutations in either their MPV17 or DGUOK genes. Each was initially investigated metabolically because of plasma methionine concentrations as high as 15-21-fold above the upper limit of the reference range, then found also to have plasma levels of S-adenosylmethionine (AdoMet) 4.4-8.6-fold above the upper limit of the reference range. Assays of S-adenosylhomocysteine, total homocysteine, cystathionine, sarcosine, and other relevant metabolites and studies of their gene encoding glycine N-methyltransferase produced evidence suggesting they had none of the known causes of elevated methionine with or without elevated AdoMet. Patient 1 grew slowly and intermittently, but was cognitively normal. At age 7 years he was found to have hepatocellular carcinoma, underwent a liver transplant and died of progressive liver and renal failure at age almost 9 years. Patient 2 had a clinical course typical of DGUOK deficiency and died at age 8 ½ months. Although each patient had liver abnormalities, evidence is presented that such abnormalities are very unlikely to explain their elevations of AdoMet or the extent of their hypermethioninemias. A working hypothesis is presented suggesting that with mitochondrial depletion the normal usage of AdoMet by mitochondria is impaired, AdoMet accumulates in the cytoplasm of affected cells poor in glycine N-methyltransferase activity, the accumulated AdoMet causes methionine to accumulate by inhibiting activity of methionine adenosyltransferase II, and that both AdoMet and methionine consequently leak abnormally into the plasma.
    Molecular Genetics and Metabolism 11/2011; 105(2):228-36. DOI:10.1016/j.ymgme.2011.11.006 · 2.63 Impact Factor
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