Deoxyguanosine Kinase Deficiency
Synonyms: DGUOK Deficiency; DGUOK-Related Mitochondrial DNA Depletion Syndrome, Hepatocerebral Form
Ayman W El-Hattab, MD, FAAP, FACMG, Fernando Scaglia, MD, FAAP, FACMG, and Lee-Jun Wong, PhD.
Author Information and AffiliationsInitial Posting: June 18, 2009; Last Update: December 22, 2016.
Estimated reading time: 15 minutes
Summary
Clinical characteristics.
The two forms of deoxyguanosine kinase (DGUOK) deficiency are a neonatal multisystem disorder and an isolated hepatic disorder that presents later in infancy or childhood. The majority of affected individuals have the multisystem illness with hepatic disease (jaundice, cholestasis, hepatomegaly, and elevated transaminases) and neurologic manifestations (hypotonia, nystagmus, and psychomotor retardation) evident within weeks of birth. Those with isolated liver disease may also have renal involvement and some later develop mild hypotonia. Progressive hepatic disease is the most common cause of death in both forms.
Diagnosis/testing.
Reduced mitochondrial (mt) DNA copy number in liver or muscle can be used to confirm mtDNA depletion. Detection of biallelic pathogenic variants in DGUOK establishes the diagnosis of DGUOK deficiency.
Management.
Treatment of manifestations: Care is best provided by a multidisciplinary team. Children with cholestatic liver disease may require formulas with enriched medium-chain-triglyceride content and fractional meals with enteral nutrition at night for adequate nutrition. Ongoing monitoring of gross motor development and skills with the intervention of appropriate therapies is appropriate in these children. Liver transplantation is controversial because of the frequent severe neurologic involvement due to the underlying mitochondrial disease.
Prevention of secondary complications: Avoidance of nutritional deficiencies; adherence to normal immunization schedule.
Surveillance: Routine monitoring of hepatic function, nutritional status, gross motor development and skills, and urine for proteinuria and aminoaciduria.
Genetic counseling.
DGUOK deficiency is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives, prenatal testing for pregnancies at increased risk, and preimplantation genetic testing are possible if the DGUOK pathogenic variants in the family are known.
Diagnosis
Suggestive Findings
The diagnosis of deoxyguanosine kinase (DGUOK) deficiency (DGUOK-related hepatocerebral mitochondrial DNA depletion syndrome) should be suspected in individuals with a combination of the following clinical, supportive laboratory, and liver biopsy findings.
Clinical features
Multisystem disease. Neonatal-onset progressive liver disease (jaundice, cholestasis, hepatomegaly, and elevated transaminases) and neurologic manifestations (hypotonia, nystagmus, and psychomotor retardation)
Isolated hepatic disease. Later-infantile or childhood-onset hepatic disease that is progressive and/or induced by viral illness
Supportive laboratory findings
Liver biopsy findings
Liver histology typically reveals cholestasis, but may show microsteatosis, fibrosis, giant cell hepatitis, or cirrhosis. Electron microscopy may reveal an increase in the number of mitochondria and abnormal cristae, findings common to all hepatocerebral mtDNA depletion syndromes [
Dimmock et al 2008b,
Al-Hussaini et al 2014].
Mitochondrial DNA content in liver tissue of affected individuals is typically less than 20% of matched control mtDNA content. Liver typically shows a combined deficiency of electron transport chain (ETC) complexes I, III, and IV [
Dimmock et al 2008b].
Establishing the Diagnosis
The diagnosis of DGUOK deficiency is established in a proband by the identification of biallelic pathogenic variants in DGUOK on molecular genetic testing (see ).
Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel or single-gene testing) and genomic testing (comprehensive genomic sequencing) depending on the phenotype.
Gene-targeted testing requires the clinician to determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of mtDNA depletion syndromes is broad, children with the distinctive clinical and laboratory findings of neonatal multisystem disease are likely to be diagnosed using gene-targeted testing (see Option 1), whereas the phenotype of those with isolated hepatic disease may be indistinguishable from many inherited disorders with liver disease and thus is more likely to be diagnosed using genomic testing (see Option 2).
Option 1
When the phenotypic and laboratory findings suggest the diagnosis of neonatal multisystem disease due to DGUOK deficiency, molecular genetic testing approaches can include single-gene testing or use of a multigene panel:
A multigene panel that includes
DGUOK and other genes of interest (see
Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic
sensitivity of the testing used for each
gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this
GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of
uncertain significance and pathogenic variants in genes that do not explain the underlying
phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused
exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include
sequence analysis,
deletion/duplication analysis, and/or other non-sequencing-based tests.
For an introduction to multigene panels click
here. More detailed information for clinicians ordering genetic tests can be found
here.
Option 2
When the phenotype is indistinguishable from many other inherited disorders with liver disease, molecular genetic testing approaches can include a combination of genomic testing (comprehensive genomic sequencing) or gene-targeted testing (multigene panel):
Comprehensive genome testing (when clinically available) includes
exome sequencing and
genome sequencing. For an introduction to comprehensive
genomic testing click
here. More detailed information for clinicians ordering genomic testing can be found
here.
Table 1.
Molecular Genetic Testing Used in DGUOK-Related Mitochondrial DNA Depletion Syndrome, Hepatocerebral Form
View in own window
| Gene 1 | Method | Proportion of Probands with Pathogenic Variants 2 Detectable by Method |
|---|
|
DGUOK
| Sequence analysis 3 | ~95% 4 |
| Gene-targeted deletion/duplication analysis 5 | ~5% 4 |
- 1.
- 2.
- 3.
- 4.
- 5.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Clinical Characteristics
Clinical Description
Deoxyguanosine kinase (DGUOK) deficiency presents in the majority of affected individuals as neonatal multisystem disease and in the minority of affected individuals later in infancy or childhood as isolated hepatic disease.
Affected sibs sharing the same pathogenic variants have exhibited multisystem disease and isolated hepatic disease with divergent long-term outcomes. Similarly, diverse long-term outcomes have been observed in affected individuals from unrelated families harboring the same pathogenic variants [Tadiboyina et al 2005].
Neonatal Multisystem Disease
Most affected infants have lactic acidosis and hypoglycemia in the first week of life. Within weeks of birth, all infants with this form of disease have hepatic disease and neurologic dysfunction.
Neurologic manifestations include hypotonia, psychomotor retardation, and typical rotary nystagmus developing into opsoclonus. Neurologic features, particularly profound hypotonia, significant psychomotor retardation, and nystagmus, are associated with poor long-term outcome [Dimmock et al 2008a].
Brain magnetic resonance imaging (MRI) is usually normal. However, subtentorial abnormal myelination and globus pallidus hyperintensity have been reported [Brahimi et al 2009].
Liver involvement includes jaundice, cholestasis, hepatomegaly, and elevated transaminases. Hepatic dysfunction progresses in the majority of children, causing neonatal- or infantile-onset liver failure with ascites, edema, and coagulopathy [Dimmock et al 2008b, Al-Hussaini et al 2014, Sezer et al 2015, McKiernan et al 2016].
The prognosis for neonatal multisystem disease is poor: most affected children die of liver failure before age four years [Sezer et al 2015].
Isolated Hepatic Disease
A minority of affected children initially presents in infancy or childhood with isolated hepatic disease manifesting as jaundice, cholestasis, hepatomegaly, and elevated transaminases. Compared to neonatal multisystem disease, this form is associated with a less severe and later-onset liver disease. The liver disease, occasionally induced by a viral illness, is typically progressive and can lead to liver failure. However, hepatic disease has undergone reversal in one individual with isolated liver disease [Mousson de Camaret et al 2007, Dimmock et al 2008b].
One individual with isolated liver disease subsequently developed hepatocellular carcinoma [Freisinger et al 2006, Grabhorn et al 2014].
Although neurologic manifestations are typically absent, long-term follow up suggests that individuals with isolated hepatic disease may subsequently develop mild hypotonia and some may also have renal involvement manifest as proteinuria and aminoaciduria [Dimmock et al 2008a].
Other less frequent manifestations. The following variable phenotypes have occasionally been reported:
Adult-onset myopathy presenting with limb weakness, ophthalmoplegia, and ptosis [
Ronchi et al 2012]
Genotype-Phenotype Correlations
No clear genotype/phenotype correlation is evident among individuals with DGUOK pathogenic missense variants. Affected sibs with the same DGUOK missense variants have exhibited divergent long-term outcomes. Similarly, diverse long-term outcomes have been observed in affected individuals from unrelated families harboring the same missense variants. These findings suggest that in individuals with pathogenic missense variants, the genotype and/or family history may not be helpful in predicting long-term outcome.
In contrast, two null variants have been typically associated with multisystem disease and a more severe clinical phenotype [Dimmock et al 2008b].
Prevalence
No large population-based studies have evaluated the prevalence of mtDNA depletion in general or DGUOK deficiency specifically. DGUOK deficiency is one of the most common causes of hepatocerebral mtDNA depletion syndromes and is estimated to account for 15%-20% of all mtDNA depletion cases [Sezer et al 2015].
Differential Diagnosis
Multisystem Disease
The neonatal multisystem form of DGUOK deficiency needs to be differentiated from other mtDNA depletion syndromes, a genetically and clinically heterogeneous group of autosomal recessive disorders that are characterized by a severe reduction in mtDNA content leading to impaired energy production in affected tissues and organs. includes the currently known mtDNA depletion syndromes.
Mitochondrial DNA depletion syndromes occur as a result of defects in mtDNA maintenance caused by pathogenic variants in nuclear genes that function in either mitochondrial nucleotide synthesis (TK2, SUCLA2, SUCLG1, RRM2B, DGUOK, and TYMP) or mtDNA replication (POLG and TWNK [formerly C10orf2]).
Mitochondrial DNA depletion syndromes are phenotypically classified into hepatocerebral, encephalomyopathic, neurogastrointestinal, and myopathic forms [El-Hattab & Scaglia 2013].
Table 3.
Mitochondrial DNA Depletion Syndromes
View in own window
| Phenotype | Gene | Mitochondrial DNA Depletion Syndrome #, Type | Reference 1 |
|---|
Hepato-
cerebral 2
|
DGUOK
| 3, hepatocerebral type | |
|
POLG
| 4A, Alpers type |
POLG-Related Disorders
|
|
MPV17
| 6, hepatocerebral type |
MPV17-Related Hepatocerebral Mitochondrial DNA Depletion Syndrome
|
| TWNK (C10orf2) | 7, hepatocerebral type | OMIM 271245 |
Encephalo-
myopathic 2
|
SUCLA2
| 5, encephalomyopathic type w/methylmalonic aciduria |
SUCLA2-Related Mitochondrial DNA Depletion Syndrome, Encephalomyopathic Form with Methylmalonic Aciduria
|
|
FBXL4
| 13, encephalomyopathic type |
FBXL4-Related Encephalomyopathic Mitochondrial DNA Depletion Syndrome
|
|
SUCLG1
| 9, encephalomyopathic type w/methylmalonic aciduria |
SUCLG1-Related Mitochondrial DNA Depletion Syndrome, Encephalomyopathic Form with Methylmalonic Aciduria
|
|
RRM2B
| 8A, encephalomyopathic type w/renal tubulopathy |
RRM2B-Related Mitochondrial Disease
|
|
OPA1
| 14, encephalocardiomyopathic type | OMIM 616896 |
Neurogastro-
intestinal 2
|
TYMP
| 1, MNGIE type |
Mitochondrial Neurogastrointestinal Encephalopathy Disease
|
|
POLG
| 4B, MNGIE type |
POLG-Related Disorders
|
|
RRM2B
| 8B, MNGIE type |
RRM2B-Related Mitochondrial Disease
|
|
Myopathic 2
|
TK2
| 2, myopathic type |
TK2-Related Mitochondrial DNA Depletion Syndrome, Myopathic Form
|
|
AGK
| 10, cardiomyopathic type (Sengers syndrome) | OMIM 212350 |
|
MGME1
| 11, myopathic type | OMIM 615084 |
|
SLC25A4
| 12B, cardiomyopathic type | OMIM 615418 |
- 1.
See hyperlinked GeneReview or OMIM phenotype entry for more information.
- 2.
Within each phenotypic category, mtDNA depletion syndromes are ordered by relative prevalence.
Isolated Hepatic Disease
The differential diagnosis of the isolated hepatic form of DGUOK deficiency involves other genetic and non-genetic age-specific causes of cholestatic liver diseases, including the following.
Genetic causes
Non-genetic causes
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with DGUOK deficiency, the following evaluations are recommended.
For both neonatal multisystem diseases and isolated hepatic disease
Evaluation of hepatic status by a physician familiar with the care of children with liver failure. Initial testing should include measurement of serum concentrations of ALT, AST, GGT, bilirubin, albumin, and coagulation profile.
Hepatic sonography and AFP to screen for hepatocellular carcinoma. AFP is a sensitive, but not specific, marker used to differentiate hepatocellular carcinoma from nonmalignant liver disease. Although the value of a highly elevated serum concentration of AFP in the detection of hepatocellular carcinoma in DGUOK deficiency is not known, the possibility of hepatocellular carcinoma should be considered in individuals with a solid tumor detected by abdominal ultrasound examination
and a highly increased serum AFP concentration [
Freisinger et al 2006].
Nutritional assessment by a dietician with experience in managing children with hepatic failure
Consultation with a clinical geneticist and/or genetic counselor
Additional evaluation for neonatal multisystem diseases
Additional evaluation for isolated hepatic disease. Urine analysis and evaluation for urine amino acids to evaluate for renal involvement
Treatment of Manifestations
Management requires a multidisciplinary team including specialists in hepatology, neurology, child development, nutrition, and clinical genetics.
Management of Neurologic Manifestations in Neonatal Multisystem Disease
Hypotonia may be significant. Therefore, ongoing monitoring of gross motor development and skills with the intervention of appropriate therapies is appropriate in these children.
Management of Liver Involvement in both Neonatal Multisystem Disease and Isolated Hepatic Disease
Management of liver disease should be guided by the results of initial evaluation in consultation with a hepatologist.
Children with cholestatic liver disease or renal disease are at significant risk of nutritional insufficiency; therefore, a dietician with experience in managing children with hepatic and renal dysfunctions should be involved in their care:
Formulas with an enriched medium-chain-triglyceride content may provide better nutritional support for infants with cholestasis than formulas with predominantly long-chain triglycerides [
Feranchak & Sokol 2007].
Cornstarch may reduce symptomatic hypoglycemia in individuals with
isolated hepatic disease.
Fractional meals and enteral nutrition during the night can result in good nutritional control [
Dimmock et al 2008b].
Affected individuals often develop life-threatening liver failure, but the benefits of liver transplantation are disputable because of the frequent severe neurologic involvement due to the underlying mitochondrial disease. A total of 14 individuals with DGUOK deficiency were reported to have undergone liver transplantation.
The one-year survival rate was 64%.
Five of the 14 survived longer than five years.
Eight of the 14 died within two years of transplantation from severe pulmonary hypertension (3/8), neurologic degeneration (2/8), procedure-related complications (2/8), and early postoperative multiorgan failure (1/8).
Although survival after liver transplantation for DGUOK deficiency is lower than survival after liver transplantation for other indications, a significant proportion of affected individuals survived more than five years despite initial neurologic abnormalities. Nevertheless, a decision to perform liver transplantation for individuals with DGUOK deficiency remains difficult because neurologic manifestations may occur and/or worsen after liver transplantation despite their absence before transplantation [
Grabhorn et al 2014].
Prevention of Secondary Complications
Nutritional deficiencies such as essential fatty acid deficiency and fat-soluble vitamin deficiency need to be prevented. Specific management requires a dietician experienced in the management of individuals with liver disease. Affected individuals need to be supplemented with fat-soluble vitamins and essential fatty acids [Feranchak & Sokol 2007].
Because they have not been associated with clinical decompensation in persons with DGUOK deficiency, routine immunizations (including influenza vaccine) are recommended at this time for all individuals with DGUOK deficiency and their household contacts.
Surveillance
No clinical guidelines for surveillance are available. The following evaluations are suggested, with frequency varying according to the severity of the condition.
Therapies Under Investigation
Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
Genetic Counseling
Genetic counseling is the process of providing individuals and families with
information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them
make informed medical and personal decisions. The following section deals with genetic
risk assessment and the use of family history and genetic testing to clarify genetic
status for family members; it is not meant to address all personal, cultural, or
ethical issues that may arise or to substitute for consultation with a genetics
professional. —ED.
Mode of Inheritance
Deoxyguanosine kinase (DGUOK) deficiency is inherited in an autosomal recessive manner.
Risk to Family Members
Parents of a proband
Sibs of a proband
Offspring of a proband. The offspring of an individual with DGUOK deficiency would be obligate heterozygotes (carriers) for a pathogenic variant in DGUOK. To date, however, fertility is unknown, as no affected individuals have reproduced.
Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a DGUOK pathogenic variant.
Carrier (Heterozygote) Detection
Carrier testing for at-risk relatives requires prior identification of the DGUOK pathogenic variants in the family.
Prenatal Testing and Preimplantation Genetic Testing
Once the DGUOK pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for DGUOK deficiency are possible.
Resources
GeneReviews staff has selected the following disease-specific and/or umbrella
support organizations and/or registries for the benefit of individuals with this disorder
and their families. GeneReviews is not responsible for the information provided by other
organizations. For information on selection criteria, click here.
American Liver Foundation
Phone: 800-465-4837 (HelpLine)
Canadian Liver Foundation
Canada
Phone: 800-563-5483
Email: clf@liver.ca
Childhood Liver Disease Research Network (ChiLDReN)
Phone: 720-777-2598
Email: joan.hines@childrenscolorado.org
Children's Liver Disease Foundation
United Kingdom
Phone: +44 (0) 121 212 3839
Email: info@childliverdisease.org
United Mitochondrial Disease Foundation
Phone: 888-317-UMDF (8633)
Email: info@umdf.org
RDCRN Patient Contact Registry: North American Mitochondrial Disease Consortium
Molecular Genetics
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.
Table A.
Deoxyguanosine Kinase Deficiency: Genes and Databases
View in own window
Data are compiled from the following standard references: gene from
HGNC;
chromosome locus from
OMIM;
protein from UniProt.
For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click
here.
Gene structure. The gene is approximately 33 kb in size and consists of seven coding exons. For a detailed summary of gene and protein information, see Table A, Gene.
Pathogenic variants. There are no common pathogenic variants or mutation hot spots [Dimmock et al 2008b].
Normal gene product. Deoxyguanosine kinase (DGUOK) is a mitochondrial protein that has a molecular weight of 28 kd with 277 amino acids.
Abnormal gene product. Missense, nonsense, and splice site variants result in a reduction or absence of DGUOK enzyme activity, which causes an imbalance of the mitochondrial deoxynucleotide pools. Because the mitochondria depend heavily on the salvage pathway for the supply of deoxynucleotides, DGUOK deficiency results in mitochondrial DNA depletion [Ashley et al 2007].
References
Literature Cited
Al-Hussaini A, Faqeih E, El-Hattab AW, Alfadhel M, Asery A, Alsaleem B, Bakhsh E, Ali A, Alasmari A, Lone K, Nahari A, Eyaid W, Al Balwi M, Craig K, Butterworth A, He L, Taylor RW. Clinical and molecular characteristics of mitochondrial DNA depletion syndrome associated with neonatal cholestasis and liver failure. J Pediatr. 2014;164:553-9.e1-2. [
PubMed: 24321534]
Ashley N, Adams S, Slama A, Zeviani M, Suomalainen A, Andreu AL, Naviaux RK, Poulton J. Defects in maintenance of mitochondrial DNA are associated with intramitochondrial nucleotide imbalances.
Hum Mol Genet. 2007;16:1400–11. [
PubMed: 17483096]
Brahimi N, Jambou M, Sarzi E, Serre V, Boddaert N, Romano S, de Lonlay P, Slama A, Munnich A, Rötig A, Bonnefont JP, Lebre AS. The first founder DGUOK mutation associated with hepatocerebral mitochondrial DNA depletion syndrome.
Mol Genet Metab. 2009;97:221–6. [
PubMed: 19394258]
Buchaklian AH, Helbling D, Ware SM, Dimmock DP. Recessive deoxyguanosine kinase deficiency causes juvenile onset mitochondrial myopathy.
Mol Genet Metab. 2012;107:92–4. [
PubMed: 22622127]
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. 2008a;14:1480–5. [
PubMed: 18825706]
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. 2008b;29:330–1. [
PubMed: 18205204]
El-Hattab AW, Scaglia F. Mitochondrial DNA depletion syndromes: review and updates of genetic basis, manifestations, and therapeutic options.
Neurotherapeutics. 2013;10:186–98. [
PMC free article: PMC3625391] [
PubMed: 23385875]
Feranchak A, Sokol R. Medical and nutritional management of cholestasis in infants and children. In: Suchy FJ, Sokol RJ, Balistreri WF, eds. Liver Disease in Children. 3 ed. New York, NY: Cambridge University Press; 2007:190-231.
Freisinger P, Fütterer 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, Horváth R. Hepatocerebral mitochondrial DNA depletion syndrome caused by deoxyguanosine kinase (DGUOK) mutations.
Arch Neurol. 2006;63:1129–34. [
PubMed: 16908739]
Grabhorn E, Tsiakas K, Herden U, Fischer L, Freisinger P, Marquardt T, Ganschow R, Briem-Richter A, Santer R. Long-term outcomes after liver transplantation for deoxyguanosine kinase deficiency: a single-center experience and a review of the literature.
Liver Transpl. 2014;20:464–72. [
PubMed: 24478274]
Hanchard NA, Shchelochkov OA, Roy A, Wiszniewska J, Wang J, Popek EJ, Karpen S, Wong LJ, Scaglia F. Deoxyguanosine kinase deficiency presenting as neonatal hemochromatosis.
Mol Genet Metab. 2011;103:262–7. [
PubMed: 21478040]
Leanza L, Ferraro P, Reichard P, Bianchi V. Metabolic interrelations within guanine deoxynucleotide pools for mitochondrial and nuclear DNA maintenance.
J Biol Chem. 2008;283:16437–45. [
PubMed: 18417473]
Lee NC, Dimmock D, Hwu WL, Tang LY, Huang WC, Chinault AC, Wong LJ. Simultaneous detection of mitochondrial DNA depletion and single-exon deletion in the deoxyguanosine gene using array-based comparative genomic hybridisation.
Arch Dis Child. 2009;94:55–8. [
PubMed: 19103789]
McKiernan P, Ball S, Santra S, Foster K, Fratter C, Poulton J, Craig K, McFarland R, Rahman S, Hargreaves I, Gupte G, Sharif K, Taylor RW. Incidence of primary mitochondrial disease in children younger than 2 years presenting with acute liver failure.
J Pediatr Gastroenterol Nutr. 2016;63:592–7. [
PMC free article: PMC5113754] [
PubMed: 27482763]
Mousson de Camaret B, Taanman JW, Padet S, Chassagne M, Mayençon 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;402:377–85. [
PMC free article: PMC1798436] [
PubMed: 17073823]
Mudd SH, Wagner C, Luka Z, Stabler SP, Allen RH, Schroer R, Wood T, Wang J, Wong LJ. Two patients with hepatic mtDNA depletion syndromes and marked elevations of S-adenosylmethionine and methionine.
Mol Genet Metab. 2012;105:228–36. [
PMC free article: PMC3264801] [
PubMed: 22137549]
Pronicka E, Węglewska-Jurkiewicz A, Taybert J, Pronicki M, Szymańska-Dębińska T, Karkucińska-Więckowska A, Jakóbkiewicz-Banecka J, Kowalski P, Piekutowska-Abramczuk D, Pajdowska M, Socha P, Sykut-Cegielska J, Węgrzyn G. 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.
J Appl Genet. 2011;52:61–6. [
PMC free article: PMC3026684] [
PubMed: 21107780]
Ronchi D, Garone C, Bordoni A, Gutierrez Rios P, Calvo SE, Ripolone M, Ranieri M, Rizzuti M, Villa L, Magri F, Corti S, Bresolin N, Mootha VK, Moggio M, DiMauro S, Comi GP, Sciacco M. Next-generation sequencing reveals DGUOK mutations in adult patients with mitochondrial DNA multiple deletions.
Brain. 2012;135:3404–15. [
PMC free article: PMC3501975] [
PubMed: 23043144]
Sezer T, Ozçay F, Balci O, Alehan F. Novel deoxyguanosine kinase gene mutations in the hepatocerebral form of mitochondrial DNA depletion syndrome.
J Child Neurol. 2015;30:124–8. [
PubMed: 24423689]
Tadiboyina VT, Rupar A, Atkison P, Feigenbaum A, Kronick J, Wang J, Hegele RA. Novel mutation in DGUOK in hepatocerebral mitochondrial DNA depletion syndrome associated with cystathioninuria.
Am J Med Genet A. 2005;135:289–91. [
PubMed: 15887277]
Vilarinho S, Sari S, Yilmaz G, Stiegler AL, Boggon TJ, Jain D, Akyol G, Dalgic B, Günel M, Lifton RP. Recurrent recessive mutation in deoxyguanosine kinase causes idiopathic noncirrhotic portal hypertension.
Hepatology. 2016;63:1977–86. [
PMC free article: PMC4874872] [
PubMed: 26874653]
Chapter Notes
Author History
David Dimmock, MD; Medical College of Wisconsin (2009-2016)
Ayman W El-Hattab, MD, FAAP, FACMG (2016-present)
Fernando Scaglia, MD, FAAP, FACMG (2009-present)
Lee-Jun Wong, PhD (2009-present)
Revision History
22 December 2016 (bp) Comprehensive update posted live
18 June 2009 (et) Review posted live
10 February 2009 (fs) Original submission
