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mitochondrial DNA depletion syndrome 3 (hepatocerebral type) - Clinical Profile, Genes & Research | Kisho | Kisho

Organ System	Phenotype Count	Example Features
Digestive system	12	Hepatic steatosis, Hepatic failure, Enlarged liver (hepatomegaly)
Lab test results	6	Elevated circulating alpha-fetoprotein concentration, Elevated circulating hepatic transaminase concentration, Decreased activity of mitochondrial complex III
Brain and nerves	5	Encephalopathy, Seizure, Polyneuropathy
Muscles	2	Low muscle tone (hypotonia), Brain shrinkage (cerebral atrophy)
Growth and development	2	Failure to thrive, Growth delay
Eyes	2	Nystagmus, Abnormal conjugate eye movement
Blood and immune system	2	Enlarged spleen (splenomegaly), Low platelet count (thrombocytopenia)
Heart and blood vessels	1	Portal hypertension
Head and neck	1	Microcephaly

Diagnosis

Drawn from GeneReviews diagnostic guidelines, newborn screening panel status (RUSP), and ClinGen gene-disease validity classifications. Reflects current clinical evidence and consensus where available.

GeneReviews

Diagnostic Criteria

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

Source: GeneReviews — "Deoxyguanosine Kinase Deficiency"

GeneReviews

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. 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 . Table 2. Mitochondrial DNA Depletion Syndromes

Phenotype1	Gene	Disorder/ Phenotype	Additional Common Manifestations2

Genetic testing for DGUOK is available. Testing is considered confirmatory for diagnosis.

Biomarker and diagnostic research for mitochondrial DNA depletion syndrome 3 (hepatocerebral type) has been reported in the published literature.

Treatment

Compiled from FDA-approved drug records, orphan drug designations, and FDA Adverse Event Reporting System (FAERS) safety data. GeneReviews management guidance is included where available.

No approved treatments are currently available for mitochondrial DNA depletion syndrome 3 (hepatocerebral type). The disease remains an area of unmet medical need.

Gene therapy approaches for mitochondrial DNA depletion syndrome 3 (hepatocerebral type) have been reported in the published literature.

GeneReviews

Management Guidelines

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 (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/Concern	Evaluation	Comment
General	Measurement of plasma lactate fasting blood sugar	In those w/neonatal multisystem disease Neurologic
Renal	Urinalysis urine amino acids to evaluate for renal involvement	In those w/isolated hepatic disease
Genetic counseling	By genetics professionals2	To inform affected persons their families re nature, MOI, implications of DGUOK deficiency to facilitate medical personal decision making Family support resources
Treatment of Manifestations in Individuals with Deoxyguanosine Kinase Deficiency Manifestation/Concern	Treatment	Considerations/Other Hypotonia/
Feeding issues	Feeding therapy; gastrostomy tube placement may be required for persistent feeding issues.

Source: GeneReviews — "Deoxyguanosine Kinase Deficiency"

Clinical Trials

View trials for mitochondrial DNA depletion syndrome 3 (hepatocerebral type)

Explore Trials

Prognosis

Based on GeneReviews surveillance recommendations, HPO phenotype frequency and severity annotations, and published prevalence estimates from Orphanet and OMIM.

GeneReviews

Surveillance Guidelines

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 are recommended. Table 5. Recommended Surveillance for Individuals with Deoxyguanosine Kinase Deficiency

System/Concern	Evaluation	Frequency
General	Monitor fasting blood sugar.	During infancy Neurodevelopment
Renal disease	Urinalysis urine amino acids for proteinuria aminoaciduria	At 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

Source: GeneReviews — "Deoxyguanosine Kinase Deficiency"

Phenotype severity distribution: 5 always present features.

Estimated prevalence: <1 in 1,000,000 (VERY_RARE).

Research Landscape

Sourced from ClinicalTrials.gov and PubMed. Publication types are classified using NLM-curated article metadata; research type breakdowns reflect the nature of published work for this disease.

No clinical trials have been registered for mitochondrial DNA depletion syndrome 3 (hepatocerebral type).

165 publications have been identified in PubMed for mitochondrial DNA depletion syndrome 3 (hepatocerebral type). Research spans Basic Science / Preclinical (33%), Review / Meta-Analysis (27%), and Epidemiology / Natural History (18%).

Research Type	Count	% of Total
Laboratory research	54	33%
Research summaries	45	27%
Disease patterns and progression	30	18%
Patient case studies	14	8%
New treatment approaches	9	5%
Testing and diagnosis research	7	4%
Clinical study results	5	3%
Other research	1	1%

Recent Publications

Oppenheimer KR (2026). [PMID: 41472381](https://pubmed.ncbi.nlm.nih.gov/41472381/). *J Clin Endocrinol Metab*. [Case Report / Case Series]
Lopriore P (2026). [PMID: 41538773](https://pubmed.ncbi.nlm.nih.gov/41538773/). *Neurology*. [Epidemiology / Natural History]
Lv S (2026). [PMID: 42072705](https://pubmed.ncbi.nlm.nih.gov/42072705/). *Biomolecules*. [Basic Science / Preclinical]
Li M (2026). [PMID: 42094628](https://pubmed.ncbi.nlm.nih.gov/42094628/). *Mol Genet Metab Rep*. [Case Report / Case Series]
Sharma R (2026). [PMID: 41653646](https://pubmed.ncbi.nlm.nih.gov/41653646/). *Neuromuscul Disord*. [Review / Meta-Analysis]
Wu JS (2026). [PMID: 40349960](https://pubmed.ncbi.nlm.nih.gov/40349960/). *J Adv Res*. [Basic Science / Preclinical]
Keser M (2026). [PMID: 40352449](https://pubmed.ncbi.nlm.nih.gov/40352449/). *Mol Syndromol*. [Basic Science / Preclinical]
Damiano M (2026). [PMID: 41729327](https://pubmed.ncbi.nlm.nih.gov/41729327/). *J Neurol*. [Basic Science / Preclinical]
Chen L (2026). [PMID: 40461781](https://pubmed.ncbi.nlm.nih.gov/40461781/). *Nat Biotechnol*. [Basic Science / Preclinical]
Liu H (2026). [PMID: 41532538](https://pubmed.ncbi.nlm.nih.gov/41532538/). *J Am Heart Assoc*. [Epidemiology / Natural History]

Kisho

mitochondrial DNA depletion syndrome 3 (hepatocerebral type)

Overview

Clinical Presentation

Clinical Guidance

Neonatal Multisystem Disease

Explore clinical features

Genetic Landscape

Diagnosis

Diagnostic Criteria

Suggestive Findings

Differential Diagnosis

Treatment

Management Guidelines

Clinical Trials

Prognosis

Surveillance Guidelines

Research Landscape

Recent Publications

Medical References

External Resources

OMIM

Orphanet

GARD

Questions for Your Care Team

Questions for Your Care Team

mitochondrial DNA depletion syndrome 3 (hepatocerebral type)

Overview

Clinical Presentation

Clinical Guidance

Neonatal Multisystem Disease

Explore clinical features

Genetic Landscape

Diagnosis

Diagnostic Criteria

Suggestive Findings

Differential Diagnosis

Treatment

Management Guidelines

Clinical Trials

Prognosis

Surveillance Guidelines

Research Landscape

Recent Publications

Medical References

External Resources

OMIM

Orphanet

GARD

Related Diseases

Questions for Your Care Team

Questions for Your Care Team