Mitochondrial DNA depletion syndrome-3 is an autosomal recessive disorder characterized by onset in infancy of progressive liver failure and neurologic abnormalities, hypoglycemia, and increased lactate in body fluids. Affected tissues show both decreased activity of the mtDNA-encoded respiratory chain ...Mitochondrial DNA depletion syndrome-3 is an autosomal recessive disorder characterized by onset in infancy of progressive liver failure and neurologic abnormalities, hypoglycemia, and increased lactate in body fluids. Affected tissues show both decreased activity of the mtDNA-encoded respiratory chain complexes (I, III, IV, and V) and mtDNA depletion (Mandel et al., 2001). For a discussion of genetic heterogeneity of autosomal recessive mtDNA depletion syndromes, see MTDPS1 (603041)
Boustany et al. (1983) reported a patient who died at age 9 months of hepatic failure with generalized aminoaciduria, but without lactic acidosis or muscle involvement. Liver biopsy showed enlarged mitochondria and decreased cytochrome c oxidase activity (less than ...Boustany et al. (1983) reported a patient who died at age 9 months of hepatic failure with generalized aminoaciduria, but without lactic acidosis or muscle involvement. Liver biopsy showed enlarged mitochondria and decreased cytochrome c oxidase activity (less than 10% of normal). Kidney mitochondria showed normal cytochromes. A second cousin, related through the maternal grandfather, had a fatal mitochondrial myopathy characterized by progressive generalized hypotonia, progressive external ophthalmoplegia, and severe lactic acidosis. In an addendum, the authors noted that another family member presented at 2 months of age with hypotonia, ophthalmoplegia, and lactic acidosis. In tissue samples from the patient reported by Boustany et al. (1983), Moraes et al. (1991) found a quantitative defect of mtDNA involving liver (12% of control values). There was no evidence of an mtDNA mutation in the areas surrounding the origin of replication of the heavy strand (H-strand) or light strand (L-strand) of mtDNA. Moraes et al. (1991) concluded that affected individuals exhibit variable levels of mtDNA depletion (up to 98%) in affected tissues, while unaffected tissues have relatively normal levels of mtDNA. In addition, different tissues may be involved in related patients. Mazziotta et al. (1992) reported a 3-month-old girl who presented with frequent vomiting and hypotonia. She had severe metabolic acidosis, hepatomegaly, and rapidly progressive fatal liver failure with death at age 4 months. Mitochondrial DNA was 90% depleted in liver and activity of mitochondrial-encoded respiratory chain enzymes were markedly decreased. Bodnar et al. (1993) studied fibroblasts from a patient described by Leonard et al. (1991). The fourth child of healthy, unrelated parents and the product of an uncomplicated full-term pregnancy, the infant soon after birth developed progressive liver failure, widespread edema, hyponatremia, hypoalbuminemia, marked prolongation of clotting times, and lactic acidosis. He became progressively more hypotonic and unresponsive and died at 4 months of age. An older sister had a clinically similar illness and died at 4 months of age. One older brother was noted to be hypertonic and jittery on the second day of life and died suddenly and unexpectedly at 4 weeks of age. Clinical presentation and family history were similar to those reported for cases of mtDNA depletion. Studies on cultured skin fibroblasts from patient 1 revealed a decrease in activities of the respiratory-chain enzymes and a quantitative decrease in mtDNA. It was also observed that the fibroblasts were dependent on uridine and pyruvate for growth, which is a well-characterized requirement for rho(0) cells, which have been depleted of mtDNA by long-term exposure to low concentrations of ethidium bromide. This property of the patient's fibroblasts provided a selectable marker for experiments performed by Bodnar et al. (1993) because complementation of these metabolic requirements indicated the reconstitution of mitochondrial function. The nuclear genome of this patient was represented by enucleated fibroblasts and human-derived rho(0) cell lines. The resulting cybrids grew in medium lacking pyruvate and uridine, indicating restoration of respiratory chain function. Taanman et al. (1997) studied myoblast cell cultures from a patient with the mtDNA depletion syndrome and demonstrated complementation by normal nuclei. The patient presented at 8 weeks of age with hypotonia, poor visual fixation, and variable lactic acidemia. He died of progressive liver failure at the age of 7.5 months. Taanman et al. (1997) stated that the mitochondrial DNA depletion syndrome had been documented in 29 children. Ducluzeau et al. (1999) described the case of a 28-month-old child who presented with a transient liver cholestasis, beginning at the age of 2 months, complicated by progressive fibrosis due to liver mtDNA depletion but without extrahepatic involvement. Lactate levels and lactate/pyruvate ratio were elevated. On the third liver biopsy, micronodular cirrhosis was fully established. Mitochondrial enzyme analyses and Southern blots were abnormal in liver, but normal in skin and skeletal muscle. Blake et al. (1999) reported 2 sibs with the disorder. In the proband, they used immunocytochemical techniques to demonstrate that the disorder was expressed in amniotic fluid cells. The proband, the second child in the family, was well at birth but developed hypoglycemia during the first 24 hours of life. Later, she developed lactic acidemia with progressive liver failure. Liver biopsy showed micronodular cirrhosis with proliferation of bile ducts and abundant neutral fat and bile pigment in hepatocytes. The activity of cytochrome c oxidase was severely depleted in liver. Assay of phosphoenolpyruvate carboxykinase (PEPCK; 261650) in liver mitochondria revealed evidence of reduced mitochondrial PEPCK activity, but PEPCK activity measured in amniotic fluid cells and fibroblasts was within normal limits. The patient died of progressive liver failure at the age of 6 months. Skeletal muscle obtained at postmortem showed relatively uniform fibers with no evidence of ragged-red fibers. There was an excess of coarse lipid droplets in many muscle fibers. Cytochrome c oxidase activity was normal and present in all fibers. The patient's elder brother was well at birth but very soon developed symptoms compatible with liver failure. Blood lactate was variably increased. The child died at the age of 7 weeks of progressive liver failure. Mandel et al. (2001) reported 19 affected members from 3 unrelated Israeli-Druze families with the hepatocerebral form of mtDNA depletion syndrome. Affected individuals presented between birth and 6 months of age with hepatic failure, severe failure to thrive, oscillating eye movements, and neurologic abnormalities, accompanied by lactic acidosis, hypoglycemia, and markedly elevated amounts of alpha-fetoprotein in plasma. Death usually occurred before 1 year of age. Enzymatic activities of the mitochondrial respiratory chain complexes containing mtDNA-encoded subunits (complexes I, III, and IV) were reduced to various extents, whereas complex II enzymatic activity, which is encoded solely by nuclear genes, was normal. Muscle tissue from 7 affected patients showed normal histology and respiratory chain complex activities. Mancuso et al. (2005) reported 2 sibs and 1 unrelated patient with hepatocerebral DNA depletion syndrome caused by mutations in the DGUOK gene. Common features included poor feeding, vomiting, failure to thrive, hypothermia, metabolic acidosis, and hypoglycemia in the neonatal period. Signs of overt liver failure developed in the first months of life with ascites, jaundice, hepatomegaly, abnormal liver function tests, hyperbilirubinemia, and coagulopathy. Liver biopsy of 2 patients showed severe micronodular cirrhosis, marked cholestasis, steatosis, hepatocellular loss, and fibrosis. Ultrastructural examination in 1 patient showed excessive and abnormal mitochondria. Liver specimens showed 84 to 90% mtDNA depletion. All patients showed variable encephalopathic signs including nystagmus, cerebral atrophy, microcephaly, hypotonia, and in 1 patient, optic dysplasia. Although 1 patient underwent liver transplantation, all 3 died by 5 months of age
In 3 Israeli-Druze kindreds with hepatocerebral mtDNA depletion syndrome-3, Mandel et al. (2001) identified a 1-bp deletion in the DGUOK gene (204delA; 601465.0001) that segregated with the disease. Western blot analysis failed to detect deoxyguanosine kinase protein in the ...In 3 Israeli-Druze kindreds with hepatocerebral mtDNA depletion syndrome-3, Mandel et al. (2001) identified a 1-bp deletion in the DGUOK gene (204delA; 601465.0001) that segregated with the disease. Western blot analysis failed to detect deoxyguanosine kinase protein in the liver of affected individuals. The main supply of deoxyribonucleotides (dNTPs) for mtDNA synthesis comes from the salvage pathway initiated by deoxyguanosine kinase and thymidine kinase-2. The association of mtDNA depletion with mutated DGUOK suggested that the salvage pathway enzymes are involved in the maintenance of balanced mitochondrial dNTP pools. In 3 (14%) of 21 patients with hepatocerebral mtDNA depletion syndrome-3, Salviati et al. (2002) identified mutations in the DGUOK gene (601465.0003-601465.0006). The findings suggested that other genes may also be responsible for mitochondrial depletion in the liver. Tadiboyina et al. (2005) reported 3 patients with the hepatocerebral form of mtDNA depletion syndrome together with cystathioninuria. All 3 children were homozygous for a D255Y mutation (601465.0007) in the DGUOK gene but had no mutations in the cystathionine gamma-lyase gene (CTH; 607657), indicating that the hepatocerebral form of mtDNA depletion syndrome might be associated with secondary cystathioninuria
The diagnosis of deoxyguanosine kinase (DGUOK) deficiency with multisystem disease is suspected in infants with early and progressive liver disease and neurologic features including hypotonia, nystagmus, and psychomotor retardation [Dimmock et al 2008a]....
Diagnosis Clinical Diagnosis The diagnosis of deoxyguanosine kinase (DGUOK) deficiency with multisystem disease is suspected in infants with early and progressive liver disease and neurologic features including hypotonia, nystagmus, and psychomotor retardation [Dimmock et al 2008a].The diagnosis of DGUOK deficiency with isolated hepatic disease later in infancy or childhood is suspected in individuals with progressive intrahepatic cholestasis or virally induced liver failure [Dimmock et al 2008a, Dimmock et al 2008b]. Testing Newborn screening. Elevated serum concentration of tyrosine or phenylalanine are non-specific abnormalities observed on newborn screening in the majority of infants with the multisystem disease form of DGUOK deficiency diagnosed in the US in the past eight years. Note: (1) Infants with DGUOK deficiency do not excrete succinylacetone in urine, which is diagnostic for tyrosinemia type 1 [Dimmock et al 2008b]. (2) When transient, elevation of serum concentration of tyrosine may be falsely attributed to transient tyrosinemia of the newborn [Lee et al 2009]. Other findings. Findings of intrahepatic cholestasis typically include [Ducluzeau et al 1999, Mandel et al 2001b, Salviati et al 2002, Taanman et al 2002, Taanman et al 2003, Filosto et al 2004, Rabinowitz et al 2004, Labarthe et al 2005, Mancuso et al 2005, Slama et al 2005, Tadiboyina et al 2005, Wang et al 2005, Freisinger et al 2006, Alberio et al 2007, Sarzi et al 2007, Dimmock et al 2008b, Lee et al 2009]: Elevations in serum concentrations of:Alanine aminotransferase (ALT) ranging from normal to 20 times the upper limit of normal (normal: <50 IU/L)Aspartate aminotransferase (AST) ranging from normal to 20 times the upper limit of normal (normal: 45 IU/L)Gammaglutamyltransferase (GGT) ranging from typically normal to twice the upper limit of normal (normal <51 IU/L)Conjugated hyperbilirubinemia ranging from 1.5- to 6-fold the upper limit of normal (normal: < 2 μmol/L); however, in most cases these elevations are typically two- to threefold the upper limit of normal Total bile acids; however, urine FAB-MS profile is not specific for an inborn error of bile acid synthesisCoagulopathySerum concentration of alpha fetoprotein (AFP) may or may not be elevated. Increased serum concentration of ferritin (normal <150 ng/ml), observed in a large number of infants, may be misdiagnosed as neonatal hemochromatosis (see Differential Diagnosis). Mitochondrial DNA (mtDNA) copy number analysis. Mitochondrial DNA depletion in affected tissues such as liver and muscle can be analyzed by real-time quantitative PCR (qPCR) or oligonucleotide array comparative genomic hybridization (oligo aCGH). Affected liver and muscle demonstrate less than 20% and 40%, respectively, of matched control mtDNA content [Dimmock et al 2008b, Lee et al 2009]. Biochemical TestingElectron Transport Chain (ETC) activityLiver typically shows a combined deficiency of ETC complexes I, III, and IV [Mandel et al 2001a, Salviati et al 2002, Mancuso et al 2005, Slama et al 2005, Wang et al 2005], but may exhibit isolated deficiency of ETC complex IV [Labarthe et al 2005]. Skeletal muscle. Activity of ETC complexes is normal in the majority of affected individuals [Mandel et al 2001b, Taanman et al 2002, Mancuso et al 2005, Freisinger et al 2006]; however, partially reduced activities of ETC complexes I, III, and IV have been detected in a few cases [Salviati et al 2002, Dimmock et al 2008b]. Note: Individuals with DGUOK deficiency have had ETC complex II deficiency [Wang et al 2005, Sarzi et al 2007], suggesting that measuring ETC activity on muscle is not helpful in the diagnosis of DGUOK deficiency.Brain. Partially reduced activities of ETC complexes I, III, and IV have been detected postmortem [Salviati et al 2002].DGUOK enzyme activity. DGUOK enzyme activity has been determined on skin fibroblasts and hepatic tissue [Mousson de Camaret et al 2007]; however, pitfalls have been described [Arnér et al 1992]. The range of enzyme activity in fibroblasts is 670-905 picomoles of deoxyguanosine phosphorylated per hour per milligram of protein and 1580-2825 picomoles of deoxyadenosine phosphorylated per hour per milligram of protein. PathologyLiver histology typically reveals microvesicular cholestasis, but may show bridging fibrosis, giant cell hepatitis, or cirrhosis. In several individuals the histopathologic picture may be more consistent with neonatal hemochromatosis (see Differential Diagnosis) [Mandel et al 2001a, Labarthe et al 2005, Freisinger et al 2006, Dimmock et al 2008b, Lee et al 2009]. Liver electron microscopy may reveal an increase in the number of mitochondria and is commonly associated with abnormal cristae, findings common to all hepatocerebral mtDNA depletion syndromes [Mandel et al 2001a]. Skeletal muscle histology is usually normal [Mandel et al 2001b, Labarthe et al 2005, Freisinger et al 2006]; however, multisystem disease may be associated with abnormal muscle histology. In one case, increased mitochondrial accumulation in several fibers with subsarcolemmal accumulation of mitochondria, cytochrome c oxidase-negative ragged red fibers, and lipid accumulation in ragged red fibers were observed [Mancuso et al 2005]. Neuropathologic examination may be normal or may reveal focal losses of Purkinje cells with Bergmann gliosis [Filosto et al 2004]. Molecular Genetic Testing Gene. DGUOK is the only gene mutated in DGUOK deficiency [Mandel et al 2001b].Clinical testing Sequence analysis of all coding exons and at least 50 bp of flanking intron sequences; mutation detection frequency is currently unknown, but appears to be close to 98% [Author, personal observation]. Deletion/duplication analysisOf approximately 50 kindreds studied to date [Dimmock et al 2008b], one was found to have deletion of a single exon of DGUOK [Lee et al 2009]. Oligo aCGH is detects intragenic deletions of DGUOK. Real-time qPCR estimates mitochondrial DNA copy number to rule out mtDNA depletion.Research testing Sequence analysis of RNA. Reverse transcription PCR analysis performed on DGUOK RNA extracted from fresh tissue, blood, or skin fibroblast cultures can identify splice-site mutations and abnormally spliced forms [Dimmock et al 2008b; Tang & Wong, unpublished data]. This analysis has been successfully employed in confirming the pathogenicity of splice-site mutations. Note: This method has not been used to detect deep intronic splicing mutations. Table 1. Summary of Molecular Genetic Testing Used in DGUOK-Related Mitochondrial DNA Depletion Syndrome, Hepatocerebral Form View in own windowGene Symbol Test MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityDGUOKSequence analysis of DNASequence variants 298%ClinicalDeletion / duplication testing 3Exonic or whole-gene deletions2%Sequence analysis of RNASplice-site mutations and abnormally spliced formsUnknownResearch only1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.3. Testing that identifies deletions/duplications not detectable by sequence analysis of genomic DNA; includes testing by oligo chromosomal microarray (CMA) and real-time qPCR.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing StrategyTo confirm/establish the diagnosis in a probandMultisystem illness Testing of mtDNA copy number in liver or muscle, if available, can be used to confirm mtDNA depletion [Dimmock et al 2008b]. If mtDNA depletion is confirmed by real-time qPCR, or if clinical suspicion is warranted without available tissue, sequence analysis should be considered. If sequence analysis does not identify two deleterious mutations, depletion/duplication analysis using oligo CMA should be performed. Note: Testing for ETC deficiencies on skeletal muscle is neither a sensitive nor specific test for DGUOK deficiency. Isolated hepatic disease. Liver biopsy may be necessary to reduce the number of alternative diagnoses under consideration [Suchy 2007] (see Differential Diagnosis). However, in order to avoid an invasive procedure in clinically unstable patients, DNA sequence analysis in blood sample may be considered.Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family. Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.Genetically Related (Allelic) Disorders Mutations in DGUOK are not associated with any other clinically recognized phenotypes.
Two forms of deoxyguanosine kinase (DGUOK) deficiency have been observed: multisystem disease in neonates and isolated hepatic disease later in infancy or childhood [Dimmock et al 2008a]. The majority of affected individuals have multisystem illness....
Natural History Two forms of deoxyguanosine kinase (DGUOK) deficiency have been observed: multisystem disease in neonates and isolated hepatic disease later in infancy or childhood [Dimmock et al 2008a]. The majority of affected individuals have multisystem illness.Affected sibs sharing the same mutations have exhibited multisystemic and isolated hepatic disease with divergent long-term outcomes [Tadiboyina et al 2005]. Similarly, diverse long-term outcomes have been observed in affected individuals from unrelated families harboring the same mutations.Multisystem Illness 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. Severe myopathy, developmental regression, and typical rotary nystagmus developing into opsoclonus are also seen. In particular, nystagmus and opsoclonus are associated with poor long-term outcome. Cholestasis is prominent early in the clinical course [Dimmock et al 2008a]. Liver involvement may cause neonatal- or infantile-onset liver failure. The liver failure is generally progressive with ascites, edema, and hemorrhage due to decrease of clotting factors. However, in one affected individual, hepatic dysfunction reversed and currently this individual continues to thrive with supportive care [Mousson de Camaret et al 2007].Isolated Hepatic DiseaseA minority of currently described affected individuals initially presents in infancy or childhood with isolated hepatic disease, occasionally following a viral illness. Some of these individuals may also have renal involvement manifest as proteinuria and aminoaciduria. No correlation is observed between the presence of this renal tubulopathy and long-term outcome [Dimmock et al 2008a].Long-term follow-up suggests that these individuals may subsequently develop mild hypotonia but otherwise have a good outcome without severe neurologic involvement [Dimmock et al 2008a]. Viral infections, such as herpes simplex infection, have been associated with acute hepatic decompensation in one kindred with isolated hepatic disease [Dimmock et al 2008b].Findings Common to Both FormsHepatic dysfunction is progressive in the majority of individuals with both forms of DGUOK deficiency and is the most common cause of death. However, hepatic disease has undergone reversal in one individual with isolated liver disease [Mousson de Camaret et al 2007]. One individual with isolated liver disease subsequently developed hepatocellular carcinoma. An abdominal mass was detected in another person with multisystemic disease prior to death [Dimmock et al 2008a].Findings Not ObservedFindings common to other forms of mtDNA depletion that are not observed in DGUOK deficiency include cardiac dysfunction or arrhythmias; seizures; elevated serum CK concentration; or abnormalities on brain imaging [Dimmock et al 2008b].
Mitochondrial DNA depletion is a significant cause of mitochondrial disease. Several other genes including MPV17, POLG, TWINKLE (C10orf2), and RRM2B are also responsible for mtDNA depletion associated with hepatoencephalopathy and may be clinically indistinguishable from deoxyguanosine kinase (DGUOK) deficiency at the time of presentation [Dimmock et al 2008b]. In contrast to Alpers syndrome caused by POLG mutations, DGUOK deficiency is not characterized by seizures or brain-imaging abnormalities [Dimmock et al 2008b]....
Differential Diagnosis Multisystem Illness Mitochondrial DNA depletion is a significant cause of mitochondrial disease. Several other genes including MPV17, POLG, TWINKLE (C10orf2), and RRM2B are also responsible for mtDNA depletion associated with hepatoencephalopathy and may be clinically indistinguishable from deoxyguanosine kinase (DGUOK) deficiency at the time of presentation [Dimmock et al 2008b]. In contrast to Alpers syndrome caused by POLG mutations, DGUOK deficiency is not characterized by seizures or brain-imaging abnormalities [Dimmock et al 2008b].In one recent study in which 50 of 100 children with multiple electron transport chain defects had a mtDNA copy number less than 35% of normal controls, 18% of those with mtDNA depletion had DGUOK mutations and 18% had POLG mutations. Among those with mtDNA depletion and hepatic dysfunction, DGUOK deficiency was the most common single cause [Sarzi et al 2007].Mutations in the complex III subunit assembly gene, BCS1L, are associated with significant hepatic dysfunction with significant cognitive impairment and renal tubulopathy. Hepatic failure and severe encephalopathy have also been associated with compound heterozygosity for two mutations in SCO1. A significant proportion of neonates with DGUOK deficiency have findings that overlap with neonatal hemochromatosis, in which salivary gland biopsy shows iron granules within the salivary gland epithelium [Smith et al 2004, Labarthe et al 2005, Dimmock et al 2008b]. Isolated Hepatic DiseaseThe primary differential diagnosis of hepatic mtDNA depletion involves other age-specific causes of cholestatic liver diseases, including: Extrahepatic biliary atresiaCholedochal cystAlagille syndromeCystic fibrosisHypothyroidismTotal parenteral nutrition (TPN) cholestasisGalactosemiaTyrosinemia type 1Citrin deficiencyInborn errors of bile acid synthesisAlpha-1 antitrypsin deficiencyNeonatal hemochromatosisNiemann-Pick disease type CAcid lipase deficiency (Wolman disease)Peroxisomal biogenesis disorders (see Rhizomelic Chondrodysplasia Punctata Type 1, Zellweger Syndrome Spectrum)Progressive familial intrahepatic cholestasisFor a more comprehensive review, readers are referred to Dr. Suchy’s introductory chapter in Liver Disease in Children [Suchy 2007].
To establish the extent of disease in an individual diagnosed with deoxyguanosine kinase (DGUOK) deficiency, the following are recommended:...
Management Evaluations Following Initial Diagnosis To establish the extent of disease in an individual diagnosed with deoxyguanosine kinase (DGUOK) deficiency, the following are recommended: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 AST, ALT, GGT, albumin and prealbumin, and coagulation profile (including PT and PTT). 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]. Note: Liver biopsy, if required for diagnosis, also allows for staging of the liver disease; however, it confers considerable risk and may not assist significantly in management.Nutritional assessment by a dietician with experience in managing children with hepatic failure Urine analysis and evaluation for urine amino acids Treatment of Manifestations Management requires a multidisciplinary team.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 [Feranchak & Sokol 2007]; therefore, a dietician with experience in managing children with hepatic and renal failure 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 [Dimmock et al 2008b]. Fractional meals and enteral nutrition during the night can result in good nutritional control [Ducluzeau et al 2002]. Orthotopic liver transplantationFor children with multisystem illness, orthotopic liver transplantation provides no survival benefit [Dimmock et al 2008a]. Several children with isolated hepatic or hepatorenal disease have had excellent ten-year survival with orthotopic liver transplantation and, thus, it is a potential therapeutic option. However, this option warrants discussion with parents: at least one child with isolated liver disease developed neurologic features after liver transplantation [Dimmock et al 2008a]. Beyond the issues surrounding hepatic dysfunction, liver transplantation may be indicated in this disease because of the potential for malignant transformation to hepatocellular carcinoma [Dimmock et al 2008b]; however, there are no clear data on the long-term risks for development of hepatocellular carcinoma in transplanted liver.The decision regarding orthotopic liver transplantation must be weighed against the known long-term risks of liver transplantation. Even in long-term survivors, hypotonia may be significant. Therefore, ongoing monitoring of gross motor development and skills with the intervention of appropriate therapies is appropriate in these children.Although it is used in other cholestatic disorders [Feranchak & Sokol 2007], ursodeoxycholic acid has no proven efficacy in this disease. The one infant with multisystemic disease did not benefit from treatment with this medication [Lee et al 2009].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. Further specific strategies are discussed by Feranchak & Sokol [2007].Because routine immunizations 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 Routine monitoring for [Feranchak & Sokol 2007, Dimmock et al 2008a]:Hepatic functionNutritional statusEvidence of myopathyGross motor development and skills Evidence of renal disease (proteinuria and aminoaciduria) Although monitoring for hepatocellular carcinoma is warranted, no surveillance protocol has been established.Agents/Circumstances to Avoid Although persons with DGUOK deficiency do not appear to develop seizures and thus are not typically treated with sodium valproate, it is prudent not to use sodium valproate as it is associated with hepatic decompensation in mitochondrial DNA depletion syndromes [Delarue et al 2000, Kayihan et al 2000, McFarland et al 2008, Uusimaa et al 2008]. No studies exist evaluating the safety of isoniazid, acetaminophen, or other medications normally associated with hepatic dysfunction in this disorder. Their use should be considered on a case-by-case basis.Evaluation of Relatives at Risk See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under Investigation To date there are no randomized controlled trials of therapy in this disorder [Dimmock et al 2008a].Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. DGUOK-Related Mitochondrial DNA Depletion Syndrome, Hepatocerebral Form: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDDGUOK2p13.1Deoxyguanosine kinase, mitochondrialDGUOK homepage - Mendelian genesDGUOKData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for DGUOK-Related Mitochondrial DNA Depletion Syndrome, Hepatocerebral Form (View All in OMIM) View in own window 251880MITOCHONDRIAL DNA DEPLETION SYNDROME 3 (HEPATOCEREBRAL TYPE); MTDPS3 601465DEOXYGUANOSINE KINASE; DGUOKNormal allelic variants. The gene is approximately 33 kb in size and consists of seven coding exons. The cDNA is approximately 1.3 kb. Pathologic allelic variants. There are no common mutations 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 mutations result in a reduction or absence of DGUOK enzyme activity. This reduced enzyme activity 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].