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progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 3 (PEOB3) - Clinical Profile, Genes & Research | Kisho | Kisho

Features include always present findings: Skeletal muscle atrophy, Difficulty swallowing (dysphagia), Ragged-red muscle fibers, and Progressive external ophthalmoplegia and others; and common findings: Elevated creatine kinase (muscle enzyme) (elevated circulating creatine kinase concentration), Dysarthria, Increased circulating lactate concentration, and Scapular winging and others.

Organ System	Phenotype Count	Example Features
Muscles	7	Skeletal muscle atrophy, Ragged-red muscle fibers, Weakness of facial musculature
Brain and nerves	2	Difficulty swallowing (dysphagia), Dysarthria
Lab test results	2	Elevated creatine kinase (muscle enzyme) (elevated circulating creatine kinase concentration), Increased circulating lactate concentration
Bones and joints	1	Skeletal muscle atrophy
Digestive system	1	Difficulty swallowing (dysphagia)
Head and neck	1	Weakness of facial musculature
Eyes	1	Ptosis

Age of onset: middle age.

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.

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 progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 3. The disease remains an area of unmet medical need.

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
Pulmonary	Pulmonary function eval	Consider referral to pulmonologist.
Neurologic	Neurologic exam	Consider referral to neurologist. EEG
Other	Consultation w/clinical geneticist /or genetic counselor	OT = occupational therapist; PT = physical therapist Treatment of Manifestations Treatment is primarily supportive; management should involve a multidisciplinary team. Table 5.

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

Clinical Trials

View trials for progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 3

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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: 9 always present features, 5 common features.

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progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 3

Overview

Clinical Presentation

Clinical Guidance

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

GARD

Questions for Your Care Team

Questions for Your Care Team

progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 3

Overview

Clinical Presentation

Clinical Guidance

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

GARD

Related Diseases

Questions for Your Care Team

Questions for Your Care Team