NORD gratefully acknowledges 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.
Summary
Thymidine kinase 2 deficiency (TK2D) was first described in 2001 in 4 children with severe muscle disease and as of 2022, there have been less than 120 patients described in the medical literature. All patients described have some degree of muscle weakness but the severity, age of onset and disease progression varies from person to person. The most common symptom is weakness of the arms and legs that gets worse over time. Breathing difficulties, weakness of the eye muscles and trouble chewing and swallowing are also common. The small number of patients and the recent discovery of TK2D make it difficult to predict the exact disease course in any given patient. TK2D is caused by genetic changes (mutations) in the TK2 gene and inherited as an autosomal recessive genetic condition.
Introduction
TK2D is one of the primary mitochondrial myopathies (PMM). PMM are a group of mitochondrial disorders that present predominantly with muscle manifestations. Mitochondria are found by the hundreds within every cell of the body. Mitochondria regulate the production of cellular energy and carry their own unique DNA known as mitochondrial DNA (mtDNA). Mitochondrial disorders can be caused by changes in genes within the mitochondria (mtDNA) or in genes outside the mitochondria (nuclear DNA). These genetic changes affect the ability of cells to produce energy. PMM can involve multiple body systems, but primarily affect the skeletal muscles. For more information, choose “primary mitochondrial myopathies” as your search term in the Rare Disease Database.
The symptoms of TK2D vary in severity, age of onset and how quickly they progress. There are three main types of TK2D: the infantile-onset type, childhood-onset type and late-onset type.
Infantile-Onset
The first symptoms of infantile-onset TK2D typically begin before one year of age. Early development and growth are normal. The first signs of TK2D are usually low muscle tone (hypotonia) and muscle weakness of the arms and legs. Other early signs include feeding problems and difficulty breathing. Some patients with infantile-onset TK2D also have a brain disease known as encephalopathy. This can lead to developmental and cognitive problems, hearing loss and seizures.
The symptoms of infantile TK2D quickly get worse over time. Most children with this condition never walk or quickly lose the ability to walk. Because the muscles associated with breathing are affected, most children eventually require ventilator support. Death due to respiratory failure usually occurs a few years after the first symptoms occur.
Childhood-Onset
Symptoms of childhood-onset TK2D appear between the ages of 1 and 12 years. The first signs are typically muscle weakness of the arms and legs. The facial muscles are also often involved leading to facial paralysis and droopy eyelids (ptosis). The muscles of the eyeballs may also be affected, leading to difficulties in moving the eyeballs (progressive external ophthalmoparesis or PEO).
Childhood-onset TK2D is slowly progressive, and most children will need a wheelchair by age 10. The respiratory muscles become weak as well, and many children will require some type of ventilator to assist with breathing. Survival is variable, but many children die from respiratory failure in their teens.
Late-Onset
Symptoms of the late-onset type of TK2D begin after age 12. The muscles of the limbs become weak, particularly shoulders, arms, hips and thighs (proximal muscle weakness). One of the first symptoms may be weakness of the shoulder muscles causing the shoulder blade to stick out (scapular winging). Facial muscle weakness can cause droopy eyelids (ptosis) and weakness of the muscles that move the eye (progressive external ophthalmoplegia or PEO). Other symptoms include difficulty swallowing and talking.
Progression is different from person to person. Generally, the symptoms of late-onset TK2D get slowly worse over time. Most people do not lose the ability to walk, but often need some kind of assistance with mobility. The respiratory muscles are affected and become weak. Many people eventually need some type of ventilator support to help with breathing. Death usually occurs 20-30 years after the onset of symptoms and is usually due to respiratory failure.
TK2D is caused by pathogenic variants (mutations) 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 non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, 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 non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.
The exact number of people with TK2D is unknown. In 2018, there were about 107 individuals reported in the medical literature with this condition. Because TK2D was first described in 2001 and is not a well-known cause of muscle weakness, it is likely that many people with this condition do not get diagnosed. 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 mutations 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 will 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/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/
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 Sept 6, 2022.
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, Mirzaa GM, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2022. Available from: https://www.ncbi.nlm.nih.gov/books/NBK114628/ Accessed Sept 6, 2022.
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 Sept 6, 2022.
MitoAction. TK2d.https://www.mitoaction.org/mitochondrial-disease/types-of-mito/tk2d/. Accessed Sept 6, 2022.
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