Deoxyguanosine Kinase Deficiency
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
- Lactic acidosis and hypoglycemia
- Elevated transaminases alanine aminotransferase (ALT) and aspartate aminotransferase (AST)
- In some cases, elevated serum gammaglutamyltransferase (GGT), alpha fetoprotein (AFP), and ferritin [Dimmock et al 2008b]
- In most cases, plasma amino acid profile showing elevated tyrosine, phenylalanine, and methionine [Leanza et al 2008, Mudd et al 2012].Note: (1) Elevated serum concentration of tyrosine or phenylalanine can be detected on newborn screening in the majority of neonates with multisystem DGUOK deficiency. (2) Infants with DGUOK deficiency do not excrete succinylacetone in the urine, whereas urinary excretion of succinylacetone is diagnostic for tyrosinemia type 1. (3) When transient, elevation of serum concentration of tyrosine may be falsely attributed to transient tyrosinemia of the newborn [Lee et al 2009].
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 Table 1).
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:
- Single-gene testing. Sequence analysis of DGUOK is performed first. If only one pathogenic variant is found, gene-targeted deletion/duplication analysis is performed next.
- 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.
- A multigene panel that includes DGUOK and other genes of interest (see Differential Diagnosis) may be considered.
Table 1.
Molecular Genetic Testing Used in DGUOK-Related Mitochondrial DNA Depletion Syndrome, Hepatocerebral Form
| 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.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on allelic variants detected in this gene.
- 3.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 4.
The Human Gene Mutation Database (HGMD)
- 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:
- Non-cirrhotic portal hypertension with onset during infancy or childhood [Vilarinho et al 2016]
- Neonatal hemochromatosis [Hanchard et al 2011, Pronicka et al 2011]
- Adult-onset myopathy presenting with limb weakness, ophthalmoplegia, and ptosis [Ronchi et al 2012]
- Juvenile-onset myopathy presenting with weakness and fatigability [Buchaklian 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. Table 3 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
| 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
- Alagille syndrome
- Cystic fibrosis
- Galactosemia
- Tyrosinemia type 1
- Citrin deficiency
- Inborn errors of bile acid synthesis
- Alpha-1 antitrypsin deficiency
- Niemann-Pick disease type C
- Acid lipase deficiency (Wolman disease)
- Peroxisomal biogenesis disorders (see Rhizomelic Chondrodysplasia Punctata Type 1, Zellweger Syndrome Spectrum)
- Progressive familial intrahepatic cholestasis
Non-genetic causes
- Extrahepatic biliary atresia
- Choledochal cyst
- Hypothyroidism
- Total parenteral nutrition (TPN) cholestasis
- Neonatal hemochromatosis
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
- Measurement of plasma lactate and fasting blood sugar
- Comprehensive neurologic examination and developmental/cognitive assessment. Neuroimaging may be considered.
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.
- Neonatal multisystem disease:
- Hepatic function
- Nutritional status
- Developmental and neurologic assessment
- AFP and hepatic sonography to monitor for hepatocellular carcinoma.
- Isolated hepatic disease
- Hepatic function
- Nutritional status
- Evidence of renal disease (proteinuria and aminoaciduria)
- AFP and hepatic sonography to monitor for hepatocellular carcinoma
Evaluation of Relatives at Risk
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
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.