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Post mortem identification of deoxyguanosine kinase (DGUOK) gene mutations combined with impaired glucose homeostasis and iron overload features in four infants with severe progressive liver failure

Deoxyguanosine kinase deficiency (dGK) is a frequent cause of the hepatocerebral form of mitochondrial depletion syndrome (MDS). A group of 28 infants with severe progressive liver failure of unknown cause was recruited for post mortem search for deoxyguanosine kinase (DGUOK) gene mutations. Four af...

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Autores principales: Pronicka, Ewa, Węglewska-Jurkiewicz, Anna, Taybert, Joanna, Pronicki, Maciej, Szymańska-Dębińska, Tamara, Karkucińska-Więckowska, Agnieszka, Jakóbkiewicz-Banecka, Joanna, Kowalski, Paweł, Piekutowska-Abramczuk, Dorota, Pajdowska, Magdalena, Socha, Piotr, Sykut-Cegielska, Jolanta, Węgrzyn, Grzegorz
Formato: Texto
Lenguaje:English
Publicado: Springer-Verlag 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3026684/
https://www.ncbi.nlm.nih.gov/pubmed/21107780
http://dx.doi.org/10.1007/s13353-010-0008-y
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author Pronicka, Ewa
Węglewska-Jurkiewicz, Anna
Taybert, Joanna
Pronicki, Maciej
Szymańska-Dębińska, Tamara
Karkucińska-Więckowska, Agnieszka
Jakóbkiewicz-Banecka, Joanna
Kowalski, Paweł
Piekutowska-Abramczuk, Dorota
Pajdowska, Magdalena
Socha, Piotr
Sykut-Cegielska, Jolanta
Węgrzyn, Grzegorz
author_facet Pronicka, Ewa
Węglewska-Jurkiewicz, Anna
Taybert, Joanna
Pronicki, Maciej
Szymańska-Dębińska, Tamara
Karkucińska-Więckowska, Agnieszka
Jakóbkiewicz-Banecka, Joanna
Kowalski, Paweł
Piekutowska-Abramczuk, Dorota
Pajdowska, Magdalena
Socha, Piotr
Sykut-Cegielska, Jolanta
Węgrzyn, Grzegorz
author_sort Pronicka, Ewa
collection PubMed
description Deoxyguanosine kinase deficiency (dGK) is a frequent cause of the hepatocerebral form of mitochondrial depletion syndrome (MDS). A group of 28 infants with severe progressive liver failure of unknown cause was recruited for post mortem search for deoxyguanosine kinase (DGUOK) gene mutations. Four affected patients (14% of the studied group), two homozygotes, one compound heterozygote, and one heterozygote, with DGUOK mutation found on only one allele, were identified. Three known pathogenic mutations in the DGUOK gene were detected, c.3G>A (p.Met1Ile), c.494A>T (p.Glu165Val), and c.766_767insGATT (p.Phe256X), and one novel molecular variant of unknown pathogeneity, c.813_814insTTT (p.Asn271_Thr272insPhe). Profound mitochondrial DNA depletion was confirmed in available specimens of the liver (4%, 15%, and 10% of the normal value) and in the muscle (4%, 23%, 45%, and 6%, respectively). The patients were born with low weights for gestational age and they presented adaptation trouble during the first days of life. Subsequently, liver failure developed, leading to death at the ages of 18, 6, 5.5, and 2.25 months, respectively. Mild neurological involvement was observed in all children (hypotonia, psychomotor retardation, and ptosis). Hypoglycemia (hypoketotic) and lactic acidosis were the constant laboratory findings. Elevated transferrin saturation, high ferritin, and alpha-fetoprotein levels resembled, in two cases, a neonatal hemochromatosis. Liver histopathology showed severe hepatic damage ranging from micronodular formation and cirrhosis to the total loss of liver architecture with diffuse fibrosis and neocholangiolar proliferation. Pancreatic islet cell hyperplasia with numerous confluent giant islets was found in both autopsied infants. Analysis of the natural history of the disease in our patients and the literature data led us to the following observations: (i) islet cell hyperplasia (and hyperinsulinism) may contribute to MDS-associated hypoglycemia; (ii) iron overload may additionally damage mtDNA-depleted tissues; (iii) low birth weight, adaptation trouble, and abnormal amino acids in newborn screening are frequent in dGK-deficient neonates.
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spelling pubmed-30266842011-02-22 Post mortem identification of deoxyguanosine kinase (DGUOK) gene mutations combined with impaired glucose homeostasis and iron overload features in four infants with severe progressive liver failure Pronicka, Ewa Węglewska-Jurkiewicz, Anna Taybert, Joanna Pronicki, Maciej Szymańska-Dębińska, Tamara Karkucińska-Więckowska, Agnieszka Jakóbkiewicz-Banecka, Joanna Kowalski, Paweł Piekutowska-Abramczuk, Dorota Pajdowska, Magdalena Socha, Piotr Sykut-Cegielska, Jolanta Węgrzyn, Grzegorz J Appl Genet Human Genetics · Short Communication Deoxyguanosine kinase deficiency (dGK) is a frequent cause of the hepatocerebral form of mitochondrial depletion syndrome (MDS). A group of 28 infants with severe progressive liver failure of unknown cause was recruited for post mortem search for deoxyguanosine kinase (DGUOK) gene mutations. Four affected patients (14% of the studied group), two homozygotes, one compound heterozygote, and one heterozygote, with DGUOK mutation found on only one allele, were identified. Three known pathogenic mutations in the DGUOK gene were detected, c.3G>A (p.Met1Ile), c.494A>T (p.Glu165Val), and c.766_767insGATT (p.Phe256X), and one novel molecular variant of unknown pathogeneity, c.813_814insTTT (p.Asn271_Thr272insPhe). Profound mitochondrial DNA depletion was confirmed in available specimens of the liver (4%, 15%, and 10% of the normal value) and in the muscle (4%, 23%, 45%, and 6%, respectively). The patients were born with low weights for gestational age and they presented adaptation trouble during the first days of life. Subsequently, liver failure developed, leading to death at the ages of 18, 6, 5.5, and 2.25 months, respectively. Mild neurological involvement was observed in all children (hypotonia, psychomotor retardation, and ptosis). Hypoglycemia (hypoketotic) and lactic acidosis were the constant laboratory findings. Elevated transferrin saturation, high ferritin, and alpha-fetoprotein levels resembled, in two cases, a neonatal hemochromatosis. Liver histopathology showed severe hepatic damage ranging from micronodular formation and cirrhosis to the total loss of liver architecture with diffuse fibrosis and neocholangiolar proliferation. Pancreatic islet cell hyperplasia with numerous confluent giant islets was found in both autopsied infants. Analysis of the natural history of the disease in our patients and the literature data led us to the following observations: (i) islet cell hyperplasia (and hyperinsulinism) may contribute to MDS-associated hypoglycemia; (ii) iron overload may additionally damage mtDNA-depleted tissues; (iii) low birth weight, adaptation trouble, and abnormal amino acids in newborn screening are frequent in dGK-deficient neonates. Springer-Verlag 2010-11-16 2011 /pmc/articles/PMC3026684/ /pubmed/21107780 http://dx.doi.org/10.1007/s13353-010-0008-y Text en © The Author(s) 2010 https://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.
spellingShingle Human Genetics · Short Communication
Pronicka, Ewa
Węglewska-Jurkiewicz, Anna
Taybert, Joanna
Pronicki, Maciej
Szymańska-Dębińska, Tamara
Karkucińska-Więckowska, Agnieszka
Jakóbkiewicz-Banecka, Joanna
Kowalski, Paweł
Piekutowska-Abramczuk, Dorota
Pajdowska, Magdalena
Socha, Piotr
Sykut-Cegielska, Jolanta
Węgrzyn, Grzegorz
Post mortem identification of deoxyguanosine kinase (DGUOK) gene mutations combined with impaired glucose homeostasis and iron overload features in four infants with severe progressive liver failure
title Post mortem identification of deoxyguanosine kinase (DGUOK) gene mutations combined with impaired glucose homeostasis and iron overload features in four infants with severe progressive liver failure
title_full Post mortem identification of deoxyguanosine kinase (DGUOK) gene mutations combined with impaired glucose homeostasis and iron overload features in four infants with severe progressive liver failure
title_fullStr Post mortem identification of deoxyguanosine kinase (DGUOK) gene mutations combined with impaired glucose homeostasis and iron overload features in four infants with severe progressive liver failure
title_full_unstemmed Post mortem identification of deoxyguanosine kinase (DGUOK) gene mutations combined with impaired glucose homeostasis and iron overload features in four infants with severe progressive liver failure
title_short Post mortem identification of deoxyguanosine kinase (DGUOK) gene mutations combined with impaired glucose homeostasis and iron overload features in four infants with severe progressive liver failure
title_sort post mortem identification of deoxyguanosine kinase (dguok) gene mutations combined with impaired glucose homeostasis and iron overload features in four infants with severe progressive liver failure
topic Human Genetics · Short Communication
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3026684/
https://www.ncbi.nlm.nih.gov/pubmed/21107780
http://dx.doi.org/10.1007/s13353-010-0008-y
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