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mitochondrial DNA depletion syndrome, myopathic form - Clinical Profile, Treatments & Trials | Kisho | Kisho

Features include always present findings: Elevated creatine kinase (muscle enzyme) (elevated circulating creatine kinase concentration), Generalized hypotonia, and Difficulty breathing due to muscle weakness (respiratory insufficiency due to muscle weakness). 26 total HPO annotations.

Organ System	Phenotype Count	Example Features
Muscles	10	Low muscle tone (hypotonia), Generalized hypotonia, Limb muscle weakness
Brain and nerves	6	Inability to walk, Seizure, Irritability
Lab test results	5	Elevated creatine kinase (muscle enzyme) (elevated circulating creatine kinase concentration), Decreased activity of mitochondrial complex III, Decreased activity of mitochondrial ATP synthase complex
Ears	1	Hearing loss (hearing impairment)
Arms and legs	1	Limb muscle weakness
Head and neck	1	Facial diplegia
Lungs and breathing	1	Difficulty breathing due to muscle weakness (respiratory insufficiency due to muscle weakness)

GeneReviews

Clinical Guidance

To date, approximately 107 individuals with molecularly confirmed TK2-related mtDNA maintenance defect have been reported [, , , , , , , , , , , ]. The clinical presentation of TK2-related mtDNA maintenance defect is variable; as understanding of the disorder increases, the phenotype continues to broaden. Table 2. Clinical Manifestations of TK2-Related Mitochondrial DNA Maintenance Defect

Age of Onset	Prevalence	Manifestation	Frequency
Age 2 years(infantile onset)	61/89 (69%)	Hypotonia	55/57 (96%) Elevated serum CK
Cognitive impairment

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

TK2-related mitochondrial DNA (mtDNA) maintenance defect comprises a phenotypic continuum ranging from severe to mild. Three main subtypes of presentation have been described:

Infantile-onset myopathy with neurologic involvement and rapid progression to early death
Juvenile/childhood onset with generalized proximal weakness and survival to adolescence or adulthood
Late-/adult-onset myopathy with facial and limb weakness and mtDNA deletions

Suggestive Findings

TK2-related mtDNA maintenance defect should be suspected in individuals with the following clinical features (by age), supportive laboratory findings, electromyography results, skeletal muscle pathology, mtDNA content (copy number) analysis, and electron transport chain activity in skeletal muscle.

Clinical Features

Source: GeneReviews — "TK2-Related Mitochondrial DNA Maintenance Defect, Myopathic Form"

GeneReviews

Differential Diagnosis

Myopathic form of TK2-related mtDNA maintenance defect needs to be differentiated from other mtDNA maintenance defects that present with myopathy (summarized in ). Myopathic mtDNA maintenance defects include a group of diseases that vary in their age of onset. Skeletal muscles are the main system involved in all of them. Cardiomyopathy can occur in some of these disorders (see Mitochondrial DNA Maintenance Defects Overview).

Table 3.

Mitochondrial DNA Maintenance Defects Presenting with Myopathy

Loss of acquired motor skills

Source: GeneReviews — "TK2-Related Mitochondrial DNA Maintenance Defect, Myopathic Form"

Genetic testing for TK2 is available. Testing is considered confirmatory for diagnosis.

Biomarker and diagnostic research for mitochondrial DNA depletion syndrome, myopathic form 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.

1 FDA-approved treatment is available for mitochondrial DNA depletion syndrome, myopathic form, including kygevvi (KYGEVVI, approved 2025). An additional 1 compound holds orphan drug designation.

Approved Therapies

Brand Name	Generic Name	Mechanism	Approved	Market Status
KYGEVVI	—	—	2025	Available

Orphan Drug Designations

The following drugs have received orphan drug designation from the FDA for mitochondrial DNA depletion syndrome, myopathic form. Orphan designation reflects regulatory interest and does not indicate approval for treatment.

Brand Name	Generic Name	Sponsor	Designated	Exclusivity End	Designation Status
Kygevvi	doxecitine and doxribtimine	UCB, Inc.	2016	—	Designated (drug approved for other indication)

Gene therapy approaches for mitochondrial DNA depletion syndrome, myopathic form have been reported in the published literature.

GeneReviews

Management Guidelines

Evaluations Following Initial Diagnosis To establish the extent of disease and needs of an individual diagnosed with TK2-related mitochondrial DNA maintenance defect, myopathic form, the following evaluations are recommended, if not completed as part of the diagnostic evaluation. Table 4. Recommended Evaluations Following Initial Diagnosis in Individuals with TK2-Related mtDNA Maintenance Defect

System/Concern	Evaluation	Comment
Growth/feeding	Assessment of chewing swallowing ability	Consider referral to OT / feeding therapist /or gastroenterologist.
Ears	Audiology eval	To assess for sensorineural hearing loss

Clinical Trials

2 trials found

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 disease-specific clinical guidelines are available; treating physicians should consider the evaluations included in . Table 6. Recommended Surveillance for Individuals with TK2-Related mtDNA Maintenance Defect

System/Concern	Evaluation	Frequency
Growth/Feeding	Assessment of nutritional status	Routine Assessment of weight gain growth parameters
Ears	Audiology evaluation2	Annually or if concerns arise
Pulmonary	Pulmonary function tests3	Depending on clinical severity Assessment of blood gases4
Neurologic	Neurodevelopmental assessments5	At each visit Particularly in infancy, childhood, and adolescence; for adults, monitor for persistent weight loss, which may indicate inadequate nutrition. 2. In those with infantile-onset disease 3. For those who are able to cooperate 4.

Source: GeneReviews — "TK2-Related Mitochondrial DNA Maintenance Defect, Myopathic Form"

Phenotype severity distribution: 3 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.

2 clinical trials registered. Interventions under study include drug therapy. Pipeline includes 1 PHASE2, 1 PHASE1. Research is sponsored by a mix of industry and academic institutions.

124 publications have been identified in PubMed for mitochondrial DNA depletion syndrome, myopathic form. Research spans Review / Meta-Analysis (45%), Basic Science / Preclinical (36%), and Case Report / Case Series (7%).

Research Type	Count	% of Total
Research summaries	56	45%
Laboratory research	45	36%
Patient case studies	9	7%
Disease patterns and progression	7	6%
Clinical study results	4	3%
Other research	1	1%
Testing and diagnosis research	1	1%
New treatment approaches	1	1%

Recent Publications

Lan SC (2026). [PMID: 42091683](https://pubmed.ncbi.nlm.nih.gov/42091683/). *Neurol Sci*. [Case Report / Case Series]
Carrera-Bastos P (2026). [PMID: 41129010](https://pubmed.ncbi.nlm.nih.gov/41129010/). *Rev Endocr Metab Disord*. [Review / Meta-Analysis]
Oppenheimer KR (2026). [PMID: 41472381](https://pubmed.ncbi.nlm.nih.gov/41472381/). *J Clin Endocrinol Metab*. [Case Report / Case Series]
Gupta S (2026). [PMID: 41027502](https://pubmed.ncbi.nlm.nih.gov/41027502/). *Am J Cardiol*. [Review / Meta-Analysis]
Moreno CAM (2026). [PMID: 42160405](https://pubmed.ncbi.nlm.nih.gov/42160405/). *J Neuromuscul Dis*. [Epidemiology / Natural History]
Mohammady RW (2026). [PMID: 42092578](https://pubmed.ncbi.nlm.nih.gov/42092578/). *Brain Res*. [Review / Meta-Analysis]
Kleefeld F (2026). [PMID: 41639907](https://pubmed.ncbi.nlm.nih.gov/41639907/). *Acta Neuropathol Commun*. [Basic Science / Preclinical]
Vakili O (2026). [PMID: 41731726](https://pubmed.ncbi.nlm.nih.gov/41731726/). *Autophagy*. [Review / Meta-Analysis]
de Souza-Lima J (2026). [PMID: 42024694](https://pubmed.ncbi.nlm.nih.gov/42024694/). *Rev Med Chil*. [Review / Meta-Analysis]
Velásquez-Esparza MM (2026). [PMID: 42174229](https://pubmed.ncbi.nlm.nih.gov/42174229/). *Handb Exp Pharmacol*. [Basic Science / Preclinical]

Kisho

mitochondrial DNA depletion syndrome, myopathic form

Overview

Clinical Presentation

Clinical Guidance

Explore clinical features

Genetic Landscape

Diagnosis

Diagnostic Criteria

Suggestive Findings

Differential Diagnosis

Treatment

Approved Therapies

Orphan Drug Designations

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, myopathic form

Overview

Clinical Presentation

Clinical Guidance

Explore clinical features

Genetic Landscape

Diagnosis

Diagnostic Criteria

Suggestive Findings

Differential Diagnosis

Treatment

Approved Therapies

Orphan Drug Designations

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