Discovering a path forward
through genetic testing for TK2d, a mitochondrial disease
Conduct genetic testing early to confirm diagnosis, and help your patients seek the care they need.
While genetic testing is a direct route to diagnosis, not all patients are on that route. Currently, only <40% (83/210) of patients receive mitochondrial DNA (mtDNA) sequencing and <19% (40/210) receive nuclear DNA (nDNA) sequencing to diagnose their mitochondrial disease.1
Other diagnostic tests are ordered much more frequently1:
(85%, 178/210)
(71%, 149/210)
(61%, 128/210)
(39%, 82/210)
Patients with TK2d and other mitochondrial diseases see an average of 8 clinicians and often receive multiple misdiagnoses before getting the right one.1
Based on 210 participants of the Rare Diseases Clinical Research Network Contact Registry who were patients with a biochemical deficiency, self-reported diagnosis of mitochondrial disease, or a caregiver-reported diagnosis.1
You can help shorten the diagnostic journey. When you suspect TK2d, order a genetic test to definitively diagnose a patient.2-4
Common tests for diagnosing TK2d
Genetic testing is essential for the definitive diagnosis of TK2d and other mitochondrial diseases.
Many neuromuscular genetic panels are not inclusive of genes that cause mitochondrial disease. If you suspect a mitochondrial disease and order a genetic test, ensure it includes TK2 and mitochondrial genes.
If you ordered genetic tests for patients in the past that did not include these genes and results were negative or inconclusive, you may need to reanalyze the original sample or re-test.
1
Whole-exome sequencing/whole-genome sequencing (NGS: Next-generation sequencing)
- Preferred method to establish a genetic diagnosis
- Widely available and becoming more affordable
- Comprehensive and capable of detecting both nuclear and mitochondrial mutations
2
Multi-gene panel (NGS)
- A genetic testing panel inclusive of many genes associated with the disease phenotype
- The genes included in a multi-gene panel may vary by lab
- If you suspect TK2d or another specific disease, make sure the associated genes are on the panel
3
Single-gene testing
- Able to capture and diagnose a defect in the TK2 gene and other mitochondrial genes
- Very specific test that only includes a single gene—you must know which gene to test
The TK2 gene is not on all of the commonly used genetic testing panels for diseases that mimic TK2d, so if TK2d is part of the differential diagnosis, it is important to confirm gene coverage before ordering a panel. It’s also important to check availability of genetic tests, as they may not be available in every location. Find more details below about each program, the genes it includes, and cost, including the possibility of low- or no-cost options.
Visit the NIH Genetic Testing Registry to find additional options inclusive of the TK2 gene.
Several genetic testing options available in the US that include the TK2 gene*:
Initiated By
Sample Source
Test Types
Initiated By
Provider
Sample Source
Blood or saliva/buccal swab
Test Types
Multi-gene panel
Initiated By
Provider
Sample Source
Blood or saliva/buccal swab
Test Types
Multi-gene panel
Initiated By
Provider
Sample Source
Blood or buccal swab
Test Types
Multi-gene panel
Initiated By
Provider
Sample Source
Blood or saliva
Test Types
Multi-gene panel
Initiated By
Provider
Sample Source
Blood or saliva/buccal swab
Test Types
Multi-gene panel
Initiated By
Patient or provider
Sample Source
Blood or saliva/buccal swab
Test Types
Multi-gene panel
Initiated By
Provider
Sample Source
Blood
Test Types
Multi-gene panel
Initiated By
Provider
Sample Source
Blood or saliva
Test Types
Multi-gene panel
In development, details to be announced.
This is not an exhaustive list of available tests for TK2d. Additionally, the following list of labs is not exhaustive either. Labs that include TK2 gene: Athena Diagnostics, Baylor Genetics, CNH Molecular Diagnostics Laboratory, Fulgent Genetics, Greenwood Genetic Center Diagnostic Laboratories, Molecular Vision Laboratory, Integrated Genetics Westborough, LabCorp (Invitae), Prevention Genetics.
- Real-time polymerase chain reaction test used to analyze mtDNA content (copy number)
Genetic testing inclusive of mitochondrial genes, including TK2, is the most direct path to diagnosis.2,5
- Helps detect myopathic changes/abnormalities
- Many patients with a mitochondrial myopathy, such as TK2d, may have normal or nonspecific changes to EMG studies
- Some patients with TK2d (78.6%, 33/42) showed myopathic changes on EMG and NCV, including polyphasic short‑duration low‑amplitude motor unit potentials10
- Not specific and not a confirmatory diagnostic test
Genetic testing inclusive of mitochondrial genes, including TK2, is the most direct path to diagnosis.2,5
EMG=electromyography; NCV=nerve conduction velocity.
- Can include blood lactate, pyruvate, serum creatine kinase, and many more
- Requires caution when interpreting findings, as any alterations identified will not be specific to a mitochondrial disease, such as TK2d. Findings are not typically diagnostic and warrant additional testing
- Results can raise suspicion of mitochondrial dysfunction
Genetic testing inclusive of mitochondrial genes, including TK2, is the most direct path to diagnosis.2,5
- A muscle biopsy may reveal the presence of ragged red fibers, COX-deficient fibers, and mtDNA depletion or deletion
- Can be painful and invasive
- Previously considered the gold standard, but is not always highly sensitive or specific about a particular mitochondrial disease, such as TK2d
- Recommended when an mtDNA depletion or deletion syndrome, such as TK2d, is suspected
Genetic testing inclusive of mitochondrial genes, including TK2, is the most direct path to diagnosis.2,5
- Mitochondrial diseases, such as TK2d, produce variable imaging abnormalities in various organs, and some patterns can be very helpful in diagnosis
- May or may not show structural alterations depending on the type of mitochondrial diseases and type of central nervous system involvement
- Not definitive for a diagnosis
Genetic testing inclusive of mitochondrial genes, including TK2, is the most direct path to diagnosis.2,5
- Grier J, Hirano M, Karaa A, et al. Diagnostic odyssey of patients with mitochondrial disease: results of a survey. Neurol Genet. 2018;4(2):e230. doi:10.1212/NXG.0000000000000230
- Nicolau S, Milone M, Liewluck T. Guidelines for genetic testing of muscle and neuromuscular junction disorders. Muscle Nerve. 2021;64(3):255-269. doi:10.1002/mus.27337
- Ng KWP, Chin HL, Chin AXY, Goh DLM. Using gene panels in the diagnosis of neuromuscular disorders: a mini-review. Front Neurol. 2022;13:997551.
- Thymidine kinase 2 deficiency. National Organization for Rare Disorders. Updated March 4, 2025. Accessed March 25, 2025. https://rarediseases.org/rare-diseases/thymidine-kinase-2-deficiency/
- Wang J, El-Hattab AW, Wong LJC. TK2-related mitochondrial DNA maintenance defect, myopathic form. In: Adam MP, Feldman J, Mirzaa GM, et al, eds. GeneReviews®. [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024.
- Parikh S, Goldstein A, Koenig MK, et al. Diagnosis and management of mitochondrial disease: a consensus statement from the Mitochondrial Medicine Society. Genet Med. 2015;17(9):689-701. doi:10.1038/gim.2014.177
- Theunissen TEJ, Nguyen M, Kamps R, et al. Whole exome sequencing is the preferred strategy to identify the genetic defect in patients with a probable or possible mitochondrial cause. Front Genet. 2018;9(400):1-17. doi:10.3389/gene.2018.00400
- Christensen KD, Dukhovny D, Siebert U, et al. Assessing the costs and cost-effectiveness of genomic sequencing. J Pers Med. 2015;5(4):470-486. doi:10.3390/jpm5040470
- UCB Data on file. 2021.
- Garone C, Taylor RW, Nascimento A, et al. Retrospective natural history of thymidine kinase 2 deficiency. J Med Genet. 2018;55(8):515-521. doi:10.1136/jmedgenet-2017-105012
- Berardo A, Domínguez-González C, Engelstad K, et al. Advances in thymidine kinase 2 deficiency: clinical aspects, translational progress, and emerging therapies. J Neuromuscul Dis. 2022;9(2):225-235.
- Invitae. Detect muscular dystrophy program. Accessed April 15, 2025. https://www.invitae.com/sponsored-testing/detect-mdys
- Invitae. Invitae Unlock™ Behind the Seizure® Program. Accessed April 15, 2025. https://www.invitae.com/us/unlock-genetic-testing/behind-the-seizure
- Invitae. Invitae epilepsy panel: test catalog. Accessed April 15, 2025. https://www.invitae.com/us/providers/test-catalog/test-03401
- United Mitochondrial Disease Foundation. Genetic testing. Accessed April 15, 2025. https://www.UMDF.org/genetictesting/
- GeneDx. Combined mito genome plus mito focused nuclear gene panel. Accessed April 15, 2025. https://providers.genedx.com/tests/detail/combined-mito-genome-plus-mito-focused-nuclear-gene-panel-736
- Variantyx. Genomic Unity® comprehensive mitochondrial disorder analysis. Accessed April 15, 2025. https://www.variantyx.com/products-services/rare-disorder-genetics/other-targeted-analyses/genomic-unity-comprehensive-mitochondrial-disorders-analysis/#7db8a2751b9a6299973404782f728f64
- Revvity. Comprehensive neuromuscular disorders panel. Accessed April 15, 2025. https://www.revvity.com/test/Comprehensive-Neuromuscular-Disorders-Panel-D4035
- Baylor Genetics. Dual genome panel by massively parallel sequencing. Accessed April 15, 2025. https://catalog.baylorgenetics.com/details/2085
- Prevention Genetics. Comprehensive neuromuscular panel. Accessed April 15, 2025. https://www.preventiongenetics.com/testInfo?val=Comprehensive-Neuromuscular-Panel
- Prevention Genetics. Chronic progressive external ophthalmoplegia (CPEO/PEO) panel. http://preventiongenetics.com/testInfo?val=Chronic-Progressive-External-Ophthalmoplegia-%28CPEO%2FPEO%29-Panel
- Invitae. Specimen and shipping requirements. Accessed April 15, 2025. https://www.invitae.com/providers/specimen-and-shipping-requirements?tab=whole-blood
- Mattman A, O'Riley M, Waters PJ, et al. Diagnosis and management of patients with mitochondrial disease. BCMJ. 2011;53(4):177-182.
- Muraresku CC, McCormick EM, Falk MJ. Mitochondrial disease: advances in clinical diagnosis, management, therapeutic development, and preventative strategies. Curr Genet Med Rep. 2018;6(2):62–72. doi:10.1007/s40142-018-0138-9
- Johns Hopkins. Muscle biopsy. 2025. Accessed February 26, 2025. https://www.hopkinsmedicine.org/health/treatment-tests-and-therapies/muscle-biopsy
- Domínguez-González C, Fernández-Torrón R, Moore U, et al. Muscle MRI characteristic pattern for late-onset TK2 deficiency diagnosis. J Neurol. 2022;269(7):3550–3562. doi:10.1007/s00415-021-10957-0
