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Deoxyguanosine Kinase Deficiency

Synonyms: DGUOK Deficiency; DGUOK-Related Mitochondrial DNA Depletion Syndrome, Hepatocerebral Form
, MD, FAAP, FACMG
Professor, Department of Clinical Sciences
College of Medicine
University of Sharjah
Sharjah, United Arab Emirates
, MD, FAAP, FACMG
Professor, Department of Molecular and Human Genetics
Baylor College of Medicine
Houston, Texas

Initial Posting: ; Last Update: February 9, 2023.

Estimated reading time: 23 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 developmental delay) 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.

The diagnosis of DGUOK deficiency is established in a proband by the identification of biallelic pathogenic variants in DGUOK on molecular genetic testing.

Management.

Treatment of manifestations: Care is best provided by a multidisciplinary team. Feeding therapy and/or gastrostomy tube as needed for feeding issues; developmental and education support. 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. Cornstarch for those with symptomatic hypoglycemia; supplementation with fat-soluble vitamins and essential fatty acids; routine immunizations for affected individuals and household contacts to prevent viral illness. Liver transplantation has been used to treat individuals without neurologic involvement or with minimal neurologic involvement. Treatment of hepatocellular carcinoma per oncologist; social work support and care coordination as needed.

Surveillance: Monitor fasting blood sugar during infancy; neurologic and developmental assessment at each visit; assess weight gain, nutritional status, and serum concentrations of ALT, AST, GGT, bilirubin, albumin, and coagulation profile at each visit; AFP and abdominal ultrasound every three months; urinalysis and urine amino acids at each visit in those with isolated hepatic disease; assess family needs at each visit.

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 a pregnancy at increased risk, and preimplantation genetic testing are possible if the DGUOK pathogenic variants in the family are known.

Diagnosis

Suggestive Findings

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. Early infantile manifestations include the following:

  • Liver disease. Jaundice, cholestasis, and hepatomegaly, progressing to liver failure
  • Neurologic manifestations. Hypotonia, nystagmus, and developmental delay

Supportive laboratory findings

  • Lactic acidosis and hypoglycemia
  • Elevated transaminases alanine aminotransferase and aspartate aminotransferase
  • In some individuals, elevated serum gammaglutamyltransferase, alpha fetoprotein, and ferritin [Dimmock et al 2008b]
  • In most individuals, 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 mitochondrial DNA (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. The liver typically shows a combined deficiency of electron transport chain 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 (or likely pathogenic) variants in DGUOK on molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of biallelic DGUOK variants of uncertain significance (or of one known DGUOK pathogenic variant and one DGUOK variant of uncertain significance) does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires the clinician to determine which gene(s) are likely involved, whereas genomic testing does not. 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 those with a phenotype of isolated hepatic disease indistinguishable from many other inherited disorders with liver disease are 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 to detect missense, nonsense, and splice site variants and small intragenic deletions/insertions. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If only one or no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications.
    Note: Targeted analysis for pathogenic variants can be performed first in individuals of Druze ancestry (see Table 6).
  • A multigene panel that includes DGUOK and other genes of interest (see Differential Diagnosis) may be considered to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. 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. (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 comprehensive genomic testing (exome sequencing, genome sequencing) or gene-targeted testing (multigene panel):

  • Comprehensive genomic testing does not require the clinician to determine which gene is likely involved. Exome sequencing is most commonly used; genome sequencing is also possible. 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 also be considered.

Table 1.

Molecular Genetic Testing Used in Deoxyguanosine Kinase Deficiency

Gene 1MethodProportion of Pathogenic Variants 2 Identified 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 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 missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

Data derived from the subscription-based professional view of Human Gene Mutation Database [Stenson et al 2020]

5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as 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 with the same pathogenic variants have exhibited both multisystem disease and isolated hepatic disease with divergent long-term outcomes. To date, more than 100 individuals have been identified with pathogenic variants in DGUOK [El-Hattab et al 2017]. The following description of the phenotypic features associated with this condition is based on these reports.

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, developmental delay, and typical rotary nystagmus developing into opsoclonus. Neurologic features, particularly profound hypotonia, significant developmental delay, and nystagmus, are associated with poor long-term outcomes [Dimmock et al 2008a].

Brain 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, Bychkov et al 2021, Doğulu et al 2021, AlMenabawy et al 2022].

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 present 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 manifesting as proteinuria and aminoaciduria [Dimmock et al 2008a].

Other Less Frequent Manifestations

The following variable phenotypes have occasionally been reported:

Genotype-Phenotype Correlations

No clear genotype-phenotype correlations are 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 with 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].

There is no clear correlation between DGUOK pathogenic variants and outcome after liver transplantation. Affected individuals with the same genotype can show good response with liver transplantation or a very poor outcome [Jankowska et al 2021].

Prevalence

No large population-based studies have evaluated the prevalence of mitochondrial DNA (mtDNA) depletion in general or DGUOK deficiency specifically. More than 100 individuals with DGUOK deficiency have been reported [El-Hattab et al 2017]. DGUOK deficiency is one of the most common causes of hepatocerebral mtDNA depletion syndromes and is estimated to account for 15%-20% of all individuals diagnosed with mtDNA depletion syndromes [Sezer et al 2015].

Differential Diagnosis

Multisystem Disease

The neonatal multisystem form of deoxyguanosine kinase (DGUOK) deficiency needs to be differentiated from other mitochondrial DNA (mtDNA) depletion syndromes, a genetically and clinically heterogeneous group of primarily autosomal recessive disorders that are characterized by a severe reduction in mtDNA content leading to impaired energy production in affected tissues and organs. Table 2 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, TYMP, and ABAT) or mtDNA synthesis (POLG, TWNK, TFAM, and RNASEH1).

Mitochondrial DNA depletion syndromes are phenotypically classified into hepatocerebral (encephalohepatopathic), encephalomyopathic, neurogastrointestinal encephalopathic, encephaloneuropathic, and myopathic forms [El-Hattab & Scaglia 2013].

Table 2.

Mitochondrial DNA Depletion Syndromes

Phenotype 1GeneDisorder / PhenotypeAdditional Common Manifestations 2
Hepatocerebral
(Encephalo-hepatopathic) 		DGUOK DGUOK deficiencyDD, hypotonia, nystagmus, lactic acidosis
POLG Alpers-Huttenlocher syndrome DD, psychomotor regression, epilepsy, hearing impairment
MPV17 MPV17 deficiency DD, hypotonia, poor weight gain, hearing impairment, lactic acidosis
TFAM Encephalohepatopathy (OMIM 617156)IUGR, hypoglycemia
TWNK Encephalohepatopathy (OMIM 271245)DD, hypotonia, lactic acidosis
Encephalo-
myopathic 		ABAT Encephalomyopathy w/↑ GABA (OMIM 613163)DD, hypotonia, epilepsy, ↑ GABA in plasma, urine, & CSF
FBXL4 FBXL4 deficiency DD, hypotonia, epilepsy, hearing impairment, lactic acidosis
OPA1 Encephalomyopathy (OMIM 616896)DD, HCM, optic atrophy
RNASEH1 Encephalomyopathy (OMIM 616479)Ophthalmoplegia, ptosis, ataxia
RRM2B RRM2B encephalomyopathic MDMD DD, hypotonia, GI dysmotility, renal tubulopathy
SUCLA2 SUCLA2 deficiency DD, hypotonia, dystonia, hearing impairment, ↑ methylmalonic acid
SUCLG1 SUCLG1 deficiency DD, hypotonia, hearing impairment, ↑ methylmalonic acid
Neurogastro-
intestinal
encephalopathic 		POLG MNGIE type 4B GI dysmotility, cachexia, peripheral neuropathy, ophthalmoplegia, muscle weakness, leukoencephalopathy 3
RRM2B MNGIE type 8B
TYMP MNGIE type 1
Myopathic AGK Sengers syndrome (OMIM 212350)Hypotonia, HCM, cataracts
MGME1 Myopathy (OMIM 615084)Ptosis, ophthalmoplegia
TK2 TK2 deficiency Hypotonia, loss of acquired motor skills
Encephalo-
neuropathic 		TWNK Infantile-onset spinocerebellar ataxia (OMIM 271245)Hypotonia, hearing impairment

CSF = cerebrospinal fluid; DD = developmental delay; GI = gastrointestinal; HCM = hypertrophic cardiomyopathy; IUGR = intrauterine growth restriction; MDMD = mitochondrial DNA maintenance defect; MNGIE = mitochondrial neurogastrointestinal encephalopathy

1.

Within each phenotypic category, mtDNA depletion syndromes are ordered by relative prevalence.

2.

Common manifestations seen in addition to the primary phenotype (i.e., in addition to encephalohepatopathy, encephalomyopathy, etc.).

3.

Leukoencephalopathy is not present in POLG-related neurogastrointestinal encephalopathy.

Isolated Hepatic Disease

The differential diagnosis of isolated hepatic disease due to DGUOK deficiency includes other genetic and non-genetic age-specific causes of cholestatic liver disease.

Genetic causes

Non-genetic causes

  • Extrahepatic biliary atresia
  • Choledochal cyst
  • Hypothyroidism
  • Total parenteral nutrition cholestasis
  • Neonatal hemochromatosis

Management

No clinical practice guidelines for deoxyguanosine kinase (DGUOK) deficiency have been published.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with DGUOK deficiency, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 3.

Recommended Evaluations Following Initial Diagnosis in Individuals with Deoxyguanosine Kinase Deficiency

System/ConcernEvaluationComment
General Measurement of plasma lactate & fasting blood sugarIn those w/neonatal multisystem disease
Neurologic
  • Comprehensive neurologic exam
  • Developmental/cognitive assessment
  • Brain MRI may be considered.
Hepatic
  • Eval of hepatic status by physician familiar w/care of children w/liver failure
  • Initial testing should incl measurement of serum concentrations of ALT, AST, GGT, bilirubin, albumin, & coagulation profile.
  • Nutritional assessment by dietician w/experience in managing children w/hepatic failure
Abdominal ultrasound & AFP to screen for HCCAFP is a sensitive, but not specific, marker to differentiate HCC from nonmalignant liver disease. 1
Renal Urinalysis & urine amino acids to evaluate for renal involvementIn those w/isolated hepatic disease
Genetic counseling By genetics professionals 2To inform affected persons & their families re nature, MOI, & implications of DGUOK deficiency to facilitate medical & personal decision making
Family support
& resources 		Assess need for:

AFP = alpha fetoprotein; ALT = alanine aminotransferase; AST = aspartate aminotransferase; GGT = gammaglutamyltransferase; HCC = hepatocellular carcinoma; MOI = mode of inheritance

1.

Although the value of a highly elevated serum 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].

2.

Medical geneticist, certified genetic counselor, certified advanced genetic nurse

Treatment of Manifestations

Management requires a multidisciplinary team including specialists in hepatology, neurology, child development, nutrition, and clinical genetics (see Table 4).

Table 4.

Treatment of Manifestations in Individuals with Deoxyguanosine Kinase Deficiency

Manifestation/ConcernTreatmentConsiderations/Other
Hypotonia /
Feeding issues 		Feeding therapy; gastrostomy tube placement may be required for persistent feeding issues.Low threshold for clinical feeding eval &/or radiographic swallowing study when showing clinical signs or symptoms of dysphagia
Developmental delay /
Intellectual disability 		See Developmental Delay / Intellectual Disability Management Issues.For those w/neonatal multisystem disease
Hepatic disease /
Nutrition 		Mgmt per hepatologist & dietician w/experience in liver disease
  • Formulas w/enriched medium-chain triglyceride content may provide better nutritional support for infants w/cholestasis than formulas w/predominantly long-chain triglycerides. 1
  • Cornstarch may ↓ symptomatic hypoglycemia in those w/isolated hepatic disease.
  • Fractional meals & enteral nutrition at night can result in good nutritional control. 2
  • Supplementation w/fat-soluble vitamins & essential fatty acids. 1
  • Liver transplantation in selected persons w/DGUOK deficiency is not contraindicated, esp in those w/o or w/minimal neurologic abnormalities.
  • Liver transplantation was performed in 20 persons w/DGUOK deficiency at age 1-18 mos. Ten individuals (50%) died 1-21 mos after transplant from procedure-related complications (renal insufficiency, intraventricular hemorrhage, sepsis, pulmonary hypertension, or peritonitis). Among survivors, 8 presented w/good psychomotor development &/or mild hypotonia, 1 presented w/moderate cognitive impairment, & 1 presented w/severe psychomotor impairment. 3
Routine immunizations (incl influenza vaccine) for all persons w/DGUOK deficiency & their household contactsHepatic disease can be induced by viral illness.
Hepatocellular carcinoma Treatment per oncologist
Family/Community
  • Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
  • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
  • Ongoing assessment of need for palliative care involvement &/or home nursing
  • Consider involvement in adaptive sports or Special Olympics.

Developmental Delay / Intellectual Disability Management Issues

The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.

Ages 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy as well as infant mental health services, special educators, and sensory impairment specialists. In the US, early intervention is a federally funded program available in all states that provides in-home services to target individual therapy needs.

Ages 3-5 years. In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed for those who qualify based on established motor, language, social, or cognitive delay. The early intervention program typically assists with this transition. Developmental preschool is center based; for children too medically unstable to attend, home-based services are provided.

All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies (US) and to support parents in maximizing quality of life. Some issues to consider:

  • IEP services:
    • An IEP provides specially designed instruction and related services to children who qualify.
    • IEP services will be reviewed annually to determine whether any changes are needed.
    • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
    • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
    • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
  • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
  • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
  • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.

Motor Dysfunction

Gross motor dysfunction

  • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
  • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
  • For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox®, anti-parkinsonian medications, or orthopedic procedures.

Fine motor dysfunction. Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function such as feeding, grooming, dressing, and writing.

Oral motor dysfunction should be assessed at each visit and clinical feeding evaluations and/or radiographic swallowing studies should be obtained for choking/gagging during feeds, poor weight gain, frequent respiratory illnesses, or feeding refusal that is not otherwise explained. Assuming that the child is safe to eat by mouth, feeding therapy (typically from an occupational or speech therapist) is recommended to help improve coordination or sensory-related feeding issues. Feeds can be thickened or chilled for safety. When feeding dysfunction is severe, an NG-tube or G-tube may be necessary.

Communication issues. Consider evaluation for alternative means of communication (e.g., augmentative and alternative communication [AAC]) for individuals who have expressive language difficulties. An AAC evaluation can be completed by a speech-language pathologist who has expertise in the area. The evaluation will consider cognitive abilities and sensory impairments to determine the most appropriate form of communication. AAC devices can range from low-tech, such as picture exchange communication, to high-tech, such as voice-generating devices. Contrary to popular belief, AAC devices do not hinder verbal development of speech, but rather support optimal speech and language development.

Surveillance

No clinical guidelines for surveillance are available. To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations in Table 5 are recommended.

Table 5.

Recommended Surveillance for Individuals with Deoxyguanosine Kinase Deficiency

System/ConcernEvaluationFrequency
General Monitor fasting blood sugar.During infancy
Neurodevelopment
  • Neurologic assessment
  • Assess developmental progress (particularly gross motor skills) & educational needs.
At each visit in those w/neonatal multisystem disease
Hepatic function & hepatocellular carcinoma
  • Assess weight gain & nutritional status.
  • Monitor serum concentrations of ALT, AST, GGT, bilirubin, albumin, & coagulation profile.
At each visit
AFP & abdominal ultrasound to monitor for HCCEvery 3 mos
Renal disease Urinalysis & urine amino acids for proteinuria & aminoaciduriaAt each visit in those w/isolated hepatic disease
Family/Community Assess family need for social work support (e.g., palliative/respite care, home nursing, other local resources), care coordination, or follow-up genetic counseling if new questions arise (e.g., family planning).At each visit

AFP = alpha fetoprotein; ALT = alanine aminotransferase; AST = aspartate aminotransferase; GGT = gammaglutamyltransferase; HCC = 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.

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

  • The parents of an affected child are presumed to be heterozygous for a DGUOK pathogenic variant.
  • Molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a DGUOK pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
    • One of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017].
    • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

  • If both parents are known to be heterozygous for a DGUOK pathogenic variant, each sib of an affected individual has at conception 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.
  • Although penetrance of DGUOK deficiency is probably complete, age of onset and severity of the clinical symptoms vary, even in the same family. Affected sibs sharing the same pathogenic variants have exhibited both multisystem disease and isolated hepatic disease with divergent long-term outcomes.
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. The offspring of an individual with DGUOK deficiency would be obligate heterozygotes 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 Detection

Carrier testing for at-risk relatives requires prior identification of the DGUOK pathogenic variants in the family.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.
  • Carrier testing for reproductive partners of known carriers should be considered, particularly if both partners are of the same ethnic background. A DGUOK founder variant has been identified in individuals of Druze ancestry (see Table 6).

Prenatal Testing and Preimplantation Genetic Testing

Once the DGUOK pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing for DGUOK deficiency are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

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

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
DGUOK 2p13​.1 Deoxyguanosine kinase, mitochondrial DGUOK database DGUOK DGUOK

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.

Table B.

OMIM Entries for Deoxyguanosine Kinase Deficiency (View All in OMIM)

251880MITOCHONDRIAL DNA DEPLETION SYNDROME 3 (HEPATOCEREBRAL TYPE); MTDPS3
601465DEOXYGUANOSINE KINASE; DGUOK

Molecular Pathogenesis

DGUOK encodes the mitochondrial enzyme deoxyguanosine kinase (DGUOK), which mediates the first step of the mitochondrial purine nucleoside salvage pathway as it phosphorylates deoxyguanosine and deoxyadenosine to deoxyguanosine monophosphate (dGMP) and deoxyadenosine monophosphate (dAMP), respectively.

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 impaired mitochondrial DNA (mtDNA) synthesis and mtDNA depletion [El-Hattab et al 2017].

Mechanism of disease causation. Loss of function

Table 6.

Notable DGUOK Pathogenic Variants

Reference SequencesDNA Nucleotide ChangePredicted Protein ChangeComment [Reference]
NM_080916​.2
NP_550438​.1 		c.255delAp.Ala86ProfsTer13Founder variant in Druze population [Mandel et al 2001]

Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

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; Baylor College of Medicine (2009-2023)

Revision History

  • 9 February 2023 (sw) Comprehensive update posted live
  • 22 December 2016 (bp) Comprehensive update posted live
  • 18 June 2009 (et) Review posted live
  • 10 February 2009 (fs) Original submission

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