- Donate
- Understanding Rare Disease
- Living with a Rare Disease
- Community Support
- Advancing Research
- Driving Policy
- Get Involved
- Rare Disease News
- Resource Library
- About Us
- For Clinicians & Researchers
- For Patient Organizations
Last updated: 3/4/2025
Years published: 2022, 2025
NORD gratefully acknowledges Gioconda Alyea, MD (FMG), MS, National Organization for Rare Disorders and Ayman W. El-Hattab, MD, FAAP, FACMG, Professor, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates, for assistance in the preparation of this report.
Advertisement
Summary
Thymidine kinase 2 deficiency (TK2D), also known as “mitochondrial DNA depletion syndrome, myopathic form” or “mitochondrial DNA depletion syndrome-2”, is a rare genetic disorder that mainly affects the muscles.
The signs and symptoms may include muscle weakness of some degree, but the severity, age of onset and progression of the disease vary from person to person. The most common symptom is weakness in the arms and legs which worsens over time. Other common symptoms include breathing difficulties, weakness in the eye muscles and trouble chewing and swallowing. Some people may have more severe symptoms at an early age, while others may have slower disease progression.
TK2D is caused by changes (variants) in a gene called TK2, which is responsible for helping mitochondria function properly. Mitochondria are tiny structures inside our cells that act as energy factories, providing power for our bodies to function. It is an autosomal recessive condition, meaning a person must inherit a disease-causing TK2 gene variant from both parents to develop the disease.
Introduction
TK2D was first identified in 2001 in four children who had severe muscle disease. Since then, a few cases have been reported in medical literature. Because the condition is so rare and was only recently discovered, doctors still do not fully understand how the disease progresses in every patient.
TK2D is classified as one of the primary mitochondrial myopathies (PMM), a group of diseases that primarily affect the muscles due to problems in the mitochondria. Mitochondria contain their own unique DNA called mitochondrial DNA (mtDNA) which helps generate energy. When a person has two TK2 gene variants, the amount of mtDNA in muscle cells decreases over time, leading to a lack of energy in the muscles and, therefore, to progressive muscle weakness.
The signs and symptoms of TK2D can vary widely from person to person in terms of severity, age of onset and how quickly they progress. TK2D is classified into three main types based on when symptoms first appear:
Infantile-onset TK2D
This form of TK2D is the most severe and begins before a child’s first birthday. Early growth and development in babies younger than 1 year are usually normal. The first symptoms may include:
Some infants with TK2D also develop encephalopathy, a brain disorder that can cause:
Symptoms worsen rapidly over time. Most children with this form never learn to walk or lose the ability to walk soon after they start walking. Breathing muscles become weaker, and most children eventually require ventilator support to help them breathe. Most children with infantile-onset TK2D typically survive only a few years, primarily due to respiratory failure.
Childhood-onset TK2D
This form of TK2D appears between ages 1 and 12 and progresses more slowly than the infantile type. The first symptoms typically include:
The disease progresses gradually and slowly, but most children need a wheelchair by age 10. Breathing muscles weaken and many children require ventilator support. Life expectancy varies, but many children live only to their teenage years due to respiratory failure.
Late-onset TK2D
This type of TK2D develops after the age of 12 and progresses more slowly than the other forms. The first signs may include:
Symptoms worsen gradually over time, but most people do not completely lose the ability to walk. Many people eventually need assistive devices for mobility. Breathing muscles weaken and many individuals require ventilator support. Most people with late-onset TK2D live 20-30 years after symptoms begin, with respiratory failure being the most common cause of death.
TK2D is caused by changes (disease-causing variants) in the thymidine kinase 2 (TK2) gene. This gene makes a protein known as thymidine kinase 2, which helps make certain types of nucleotides which are the building blocks for DNA needed to maintain mitochondrial DNA. When the TK2 gene is not working correctly, the amount of mitochondrial DNA inside each mitochondrion decreases over time. The mitochondria are slowly unable to make energy for the body cells. This leads to progressive muscle weakness of the limbs, face, respiratory tract and other parts of the body.
TK2D deficiency is inherited in a recessive pattern. Recessive genetic disorders occur when an individual inherits a disease-causing gene variant from each parent. If an individual receives one normal gene and one disease-causing gene variant, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the gene variant and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
Mitochondrial diseases (MDs) are rare, with an estimated prevalence of 11.5 per 100,000 people. Estimating the prevalence of TK2D is difficult due to its recent characterization and lack of awareness, leading to underdiagnosis.
Based on the prevalence of broader mitochondrial disease categories, researchers estimate that TK2D affects between 600 and 2,700 people in the United States. TK2D doesn’t seem to occur more often in any one ethnic group or sex.
TK2D is diagnosed based on symptoms, a detailed patient history, clinical exam and both laboratory and genetic tests. Genetic testing for variants in the TK2 gene can confirm the diagnosis.
Other testing that may be done to support the diagnosis of TK2D includes creatine kinase (CK) that is typically elevated in blood. Electromyography (EMG) can show changes in muscle functions (myopathic changes).
There is no cure TK2D. Treatment is focused on managing the symptoms. This typically involves a team of specialists including a neurologist, pulmonologist and physical and occupational therapists. Some patients require a wheelchair for mobility. In addition, many people with TK2D need ventilator support to help with breathing.
Genetic counseling is recommended for individuals with TK2D and their families.
An investigational therapy consisting of various combinations of deoxynucleosides has been shown to improve outcomes in patients with TK2D. Deoxynucleosides are the building blocks for mitochondrial DNA. Gene therapy is also being considered as a treatment for this condition.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
JOURNAL ARTICLES
Berardo A, Domínguez-González C, Engelstad K, Hirano M. Advances in thymidine kinase 2 deficiency: clinical aspects, translational progress, and emerging therapies. J Neuromuscul Dis. 2022;9(2):225-235.
Lopez-Gomez C, Sanchez-Quintero MJ, Lee EJ, Kleiner A, et al. Synergistic deoxynucleoside and gene therapies for thymidine kinase 2 deficiency. Ann. Neurol. 2021; 90: 640-652. Note: Erratum: Ann. Neurol. 2022; 91: 303.
Domínguez-González C, Madruga-Garrido M, Hirano M, Martí I, et al. Collaborative model for diagnosis and treatment of very rare diseases: experience in Spain with thymidine kinase 2 deficiency. Orphanet J Rare Dis. 2021 Oct 2;16(1):407.
de Fuenmayor-Fernández de la Hoz CP, Morís G, Jiménez-Mallebrera C, Badosa C et al. Recurrent rhabdomyolysis and exercise intolerance: A new phenotype of late-onset thymidine kinase 2 deficiency. Mol Genet Metab Rep. 2021 Jan 6;26:100701.
Domínguez-González C, Hernández-Laín A, Rivas E, Hernández-Voth A, et al. Late-onset thymidine kinase 2 deficiency: a review of 18 cases. Orphanet J Rare Dis. 2019 May 6;14(1):100.
de Barcelos IP, Emmanuele V, Hirano M. Advances in primary mitochondrial myopathies. Curr Opin Neurol. 2019 Oct;32(5):715-721.
Garone C, Taylor RW, Nascimento A, et al. Retrospective natural history of thymidine kinase 2 deficiency. J Med Genet. 2018 Aug;55(8):515-521.
Mazurova S, Magner M, Kucerova-Vidrova V, Vondrackova A, et al. Thymidine kinase 2 and alanyl-tRNA synthetase 2 deficiencies cause lethal mitochondrial cardiomyopathy: case reports and review of the literature. Cardiol Young. 2017 Jul;27(5):936-944.
Parikh S, Goldstein A, Karaa A, et al. Patient care standards for primary mitochondrial disease: a consensus statement from the Mitochondrial Medicine Society. Genet Med. 2017;19(12):1380.
Saada A, Shaag A, Mandel H, Nevo Y, et al. Mutant mitochondrial thymidine kinase in mitochondrial DNA depletion myopathy. Nat Genet. 2001;29:342–4.
INTERNET
Mitochondrial DNA Depletion Syndrome 2. Online Mendelian Inheritance in Man, OMIM. Johns Hopkins University, Baltimore, MD. MIM Number: 609560. Last edited 06/17/2022 https://www.omim.org/entry/609560 Accessed Jan 30, 2025.
Wang J, El-Hattab AW, Wong LJC. TK2-Related Mitochondrial DNA Maintenance Defect, Myopathic Form. 2012 Dec 6 [Updated 2018 Jul 26]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. Available from: https://www.ncbi.nlm.nih.gov/books/NBK114628/ Accessed Jan 30, 2025.
TK2-related mitochondrial DNA depletion syndrome, myopathic form. MedlinePlus. Updated Sept 1, 2013. Available from:
https://medlineplus.gov/genetics/condition/tk2-related-mitochondrial-dna-depletion-syndrome-myopathic-form/ Accessed Jan 30, 2025.
NORD strives to open new assistance programs as funding allows. If we don’t have a program for you now, please continue to check back with us.
NORD and MedicAlert Foundation have teamed up on a new program to provide protection to rare disease patients in emergency situations.
Learn more https://rarediseases.org/patient-assistance-programs/medicalert-assistance-program/Ensuring that patients and caregivers are armed with the tools they need to live their best lives while managing their rare condition is a vital part of NORD’s mission.
Learn more https://rarediseases.org/patient-assistance-programs/rare-disease-educational-support/This first-of-its-kind assistance program is designed for caregivers of a child or adult diagnosed with a rare disorder.
Learn more https://rarediseases.org/patient-assistance-programs/caregiver-respite/One in 10 Americans lives with rare disease, many of whom fight a daily battle to access the care and support they need. Your gift to the National Organization for Rare Disorders (NORD®) funds life-changing programs and helps us advance policies and research to ensure that everyone gets the care they need AND deserve.