Thymidine Kinase 2 Deficiency

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.

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.

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.

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.

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.

Symptoms of the following disorders can be similar to those of thymidine kinase 2 deficiency. Comparisons may be useful for a differential diagnosis:

Spinal muscular atrophy (SMA) refers to a group of genetic disorders caused by loss of nerve cells in the spinal cord called lower motor neurons or anterior horn cells. The loss of lower motor neurons leads to progressive muscle weakness, muscle wasting (atrophy) and low muscle tone (hypotonia) that mainly affects the muscles of the shoulders, hips and back. The muscles that control feeding, swallowing and breathing can also be affected. There are at least 5 types of SMA which vary in severity and age at onset. All types of SMA are inherited in a recessive pattern. For more information, choose “spinal muscular atrophy” as your search term in the Rare Disease Database.

Facioscapulohumeral dystrophy (FSHD) is characterized by muscle weakness and wasting (atrophy). The muscles most affected are those in the face (facio), around the shoulder blades (scapulo) and in the upper arms (humeral). Over time, other muscles may become affected as well. Symptoms usually appear before age 20 but can begin in infancy or later in adulthood. FSHD typically gets slowly worse over time. Symptoms and severity vary even among affected members of the same family. Life expectancy is not shortened. FSHD is usually inherited in an autosomal dominant pattern. For more information, choose “primary mitochondrial myopathies” as your search term in the Rare Disease Database.

Chronic progressive external ophthalmoplegia (CPEO) is progressive weakness of the muscles involved in eye and eyelid movement. Signs and symptoms usually begin in early adulthood and can include weakness or paralysis of the muscles that move the eye (ophthalmoplegia) and drooping of the eyelids (ptosis). Some individuals also have weakness of the skeletal muscles (myopathy) which may be especially noticeable during exercise. CPEO can occur alone or as part of another condition. For more information, choose “chronic progressive external ophthalmoplegia” as your search term in the Rare Disease Database.

Kearns-Sayre syndrome is characterized by droopy eyelids, paralysis of the muscles that control the eyes (chronic progressive external ophthalmoplegia or CPEO) and heart disease. In addition, abnormal accumulation of pigment in the retina of the eyes can occur, leading to poor night vision and vision loss. Other findings may include muscle weakness, short stature, sensorineural hearing loss and involuntary movements. Symptoms tend to get worse over time. In some people, KSS may be part of another condition. KSS is caused by mutations in a gene found in mitochondrial DNA and is inherited in a mitochondrial pattern. For more information, choose “Kearns Sayre syndrome” as your search term in the Rare Disease Database.

MELAS (mitochondrial encephalopathy, lactic acidosis and stroke-like episodes) syndrome affects primarily the brain and the muscles. It is characterized by stroke-like episodes that lead to headaches, seizures and temporary muscle weakness. Other symptoms include loss of motor and cognitive skills and vision and hearing loss. Symptoms usually begin in childhood. Most cases of MELAS are caused by mutations in mitochondrial DNA and are inherited in a mitochondrial pattern. For more information, choose “MELAS syndrome” as your search term in the Rare Disease Database.

MERRF (myoclonus epilepsy with ragged-red fibers) syndrome is a rare disorder that affects the nervous system, skeletal muscles and other body systems. Symptoms can begin at any age. People with MERRF develop muscle jerking (myoclonus) that can affect the limbs or entire body. They may also have seizures, uncoordinated movements (ataxia), muscle weakness (myopathy), difficulty exercising and a slow loss of intellectual function (dementia). Short stature, vision problems (optic atrophy), hearing loss, weak heart muscles (cardiomyopathy) and abnormal sensation from nerve damage (peripheral neuropathy) are other common symptoms. MERRF is inherited in a mitochondrial pattern. For more information, choose “MERRF syndrome” as your search term in the Rare Disease Database.

Pompe disease is a rare progressive neurodegenerative disorder that affects many body systems. Symptoms can begin at any age and include muscle weakness that affects mobility and breathing. There are several types of Pompe disease. The most common and most severe type is the early-onset form. Infants with this form develop symptoms of muscle weakness by three months of age and have a characteristic heart defect known as hypertrophic cardiomyopathy. The symptoms of Pompe disease tend to get worse over time. This condition is inherited in a recessive pattern. For more information, choose “Pompe disease” as your search term in the Rare Disease Database.

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://nord1dev.wpengine.com/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.