Deoxyguanosine kinase deficiency

Deoxyguanosine kinase deficiency is an inherited disorder that can cause liver disease and neurological problems. Researchers have described two forms of this disorder. The majority of affected individuals have the more severe form, which is called hepatocerebral because of the serious problems it causes in the liver and brain.

Newborns with the hepatocerebral form of deoxyguanosine kinase deficiency may have a buildup of lactic acid in the body (lactic acidosis) within the first few days after birth. They may also have weakness, behavior changes such as poor feeding and decreased activity, and vomiting. Affected newborns sometimes have low blood glucose (hypoglycemia) as a result of liver dysfunction. During the first few weeks of life they begin showing other signs of liver disease which may result in liver failure. They also develop progressive neurological problems including very weak muscle tone (severe hypotonia), abnormal eye movements (nystagmus) and the loss of skills they had previously acquired (developmental regression). Children with this form of the disorder usually do not survive past the age of 2 years.

Some individuals with deoxyguanosine kinase deficiency have a milder form of the disorder without severe neurological problems. Liver disease is the primary symptom of this form of the disorder, generally becoming evident during infancy or childhood. Occasionally it first appears after an illness such as a viral infection. Affected individuals may also develop kidney problems. Mild hypotonia is the only neurological effect associated with this form of the disorder.

The prevalence of deoxyguanosine kinase deficiency is unknown. Approximately 100 affected individuals have been identified.

The DGUOK gene provides instructions for making the enzyme deoxyguanosine kinase. This enzyme plays a critical role in mitochondria, which are structures within cells that convert the energy from food into a form that cells can use. Mitochondria each contain a small amount of DNA, known as mitochondrial DNA or mtDNA, which is essential for the normal function of these structures. Deoxyguanosine kinase is involved in producing and maintaining the building blocks of mitochondrial DNA.

Mutations in the DGUOK gene reduce or eliminate the activity of the deoxyguanosine kinase enzyme. Reduced enzyme activity leads to problems with the production and maintenance of mitochondrial DNA. A reduction in the amount of mitochondrial DNA (known as mitochondrial DNA depletion) impairs mitochondrial function in many of the body's cells and tissues. These problems lead to the neurological and liver dysfunction associated with deoxyguanosine kinase deficiency.

Genetic Testing Information

• Genetic Testing Registry: Mitochondrial DNA depletion syndrome 3 (hepatocerebral type)

Genetic and Rare Diseases Information Center

• Mitochondrial DNA depletion syndrome
• Mitochondrial DNA depletion syndrome, hepatocerebral form due to DGUOK deficiency

Patient Support and Advocacy Resources

• National Organization for Rare Disorders (NORD)

Catalog of Genes and Diseases from OMIM

• MITOCHONDRIAL DNA DEPLETION SYNDROME 3 (HEPATOCEREBRAL TYPE); MTDPS3

Scientific Articles on PubMed

• PubMed

• Alberio S, Mineri R, Tiranti V, Zeviani M. Depletion of mtDNA: syndromes and genes. Mitochondrion. 2007 Feb-Apr;7(1-2):6-12. doi: 10.1016/j.mito.2006.11.010. Epub 2006 Dec 5. Citation on PubMed
• Brahimi N, Jambou M, Sarzi E, Serre V, Boddaert N, Romano S, de Lonlay P, Slama A, Munnich A, Rotig A, Bonnefont JP, Lebre AS. The first founder DGUOK mutation associated with hepatocerebral mitochondrial DNA depletion syndrome. Mol Genet Metab. 2009 Jul;97(3):221-6. doi: 10.1016/j.ymgme.2009.03.007. Epub 2009 Mar 27. Citation on PubMed
• Copeland WC. Inherited mitochondrial diseases of DNA replication. Annu Rev Med. 2008;59:131-46. doi: 10.1146/annurev.med.59.053006.104646. Citation on PubMed or Free article on PubMed Central
• Dimmock DP, Dunn JK, Feigenbaum A, Rupar A, Horvath R, Freisinger P, Mousson de Camaret B, Wong LJ, Scaglia F. Abnormal neurological features predict poor survival and should preclude liver transplantation in patients with deoxyguanosine kinase deficiency. Liver Transpl. 2008 Oct;14(10):1480-5. doi: 10.1002/lt.21556. Citation on PubMed
• Dimmock DP, Zhang Q, Dionisi-Vici C, Carrozzo R, Shieh J, Tang LY, Truong C, Schmitt E, Sifry-Platt M, Lucioli S, Santorelli FM, Ficicioglu CH, Rodriguez M, Wierenga K, Enns GM, Longo N, Lipson MH, Vallance H, Craigen WJ, Scaglia F, Wong LJ. Clinical and molecular features of mitochondrial DNA depletion due to mutations in deoxyguanosine kinase. Hum Mutat. 2008 Feb;29(2):330-1. doi: 10.1002/humu.9519. Citation on PubMed
• El-Hattab AW, Scaglia F. Deoxyguanosine Kinase Deficiency. 2009 Jun 18 [updated 2023 Feb 9]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from http://www.ncbi.nlm.nih.gov/books/NBK7040/ Citation on PubMed
• Freisinger P, Futterer N, Lankes E, Gempel K, Berger TM, Spalinger J, Hoerbe A, Schwantes C, Lindner M, Santer R, Burdelski M, Schaefer H, Setzer B, Walker UA, Horvath R. Hepatocerebral mitochondrial DNA depletion syndrome caused by deoxyguanosine kinase (DGUOK) mutations. Arch Neurol. 2006 Aug;63(8):1129-34. doi: 10.1001/archneur.63.8.1129. Citation on PubMed
• Labarthe F, Dobbelaere D, Devisme L, De Muret A, Jardel C, Taanman JW, Gottrand F, Lombes A. Clinical, biochemical and morphological features of hepatocerebral syndrome with mitochondrial DNA depletion due to deoxyguanosine kinase deficiency. J Hepatol. 2005 Aug;43(2):333-41. doi: 10.1016/j.jhep.2005.03.023. Citation on PubMed
• Mandel H, Szargel R, Labay V, Elpeleg O, Saada A, Shalata A, Anbinder Y, Berkowitz D, Hartman C, Barak M, Eriksson S, Cohen N. The deoxyguanosine kinase gene is mutated in individuals with depleted hepatocerebral mitochondrial DNA. Nat Genet. 2001 Nov;29(3):337-41. doi: 10.1038/ng746. Erratum In: Nat Genet 2001 Dec;29(4):491. Citation on PubMed
• Mousson de Camaret B, Taanman JW, Padet S, Chassagne M, Mayencon M, Clerc-Renaud P, Mandon G, Zabot MT, Lachaux A, Bozon D. Kinetic properties of mutant deoxyguanosine kinase in a case of reversible hepatic mtDNA depletion. Biochem J. 2007 Mar 1;402(2):377-85. doi: 10.1042/BJ20060705. Citation on PubMed or Free article on PubMed Central
• Saada-Reisch A. Deoxyribonucleoside kinases in mitochondrial DNA depletion. Nucleosides Nucleotides Nucleic Acids. 2004 Oct;23(8-9):1205-15. doi: 10.1081/NCN-200027480. Citation on PubMed
• Shieh JT, Berquist WE, Zhang Q, Chou PC, Wong LJ, Enns GM. Novel deoxyguanosine kinase gene mutations and viral infection predispose apparently healthy children to fulminant liver failure. J Pediatr Gastroenterol Nutr. 2009 Jul;49(1):130-2. doi: 10.1097/MPG.0b013e31819de7a6. No abstract available. Citation on PubMed
• Slama A, Giurgea I, Debrey D, Bridoux D, de Lonlay P, Levy P, Chretien D, Brivet M, Legrand A, Rustin P, Munnich A, Rotig A. Deoxyguanosine kinase mutations and combined deficiencies of the mitochondrial respiratory chain in patients with hepatic involvement. Mol Genet Metab. 2005 Dec;86(4):462-5. doi: 10.1016/j.ymgme.2005.09.006. Epub 2005 Nov 2. Citation on PubMed