Join us, and together we’ll take on TK2 deficiency.
Thymidine kinase 2-related mitochondrial DNA depletion syndrome, TK2 deficiency (TK2d), or MTDPS2, is an ultra-rare genetic disease.
We are beginning to understand the natural history of TK2d. In 2001, the TK2 gene was first linked to the disorder in children. Since 2001, there have been significant improvements in genetic testing, and some of the mutations that cause TK2d have been identified. This increase in genetic knowledge led to an identification of an adult form in 2013. However, given the continuous discovery of new mutations that can cause TK2d and the recent identification of an adult form, it is thought that TK2d is significantly underdiagnosed and underrecognized. The hope is that with advanced genetic testing, we can identify patients who are currently undiagnosed.
We need your help as we take on TK2d
Together, we are creating a TK2d registry to help build a community that may lead to better understanding of the disease and will advance therapies through clinical trials. Please help us by joining. Sign up for the Healthcare Professionl (HCP) registry HERE.
TK2 deficiency is a form of mitochondrial DNA (mtDNA) depletion syndrome (mtDNA depletion disorder or maintenance defect) caused by impaired mtDNA synthesis. This impairment can lead to mtDNA deletions as well as depletion. When mtDNA is depleted or damaged, mitochondria are unable to effectively produce the adenosine triphosphate (ATP) energy required for normal cellular function.
TK2 is required to maintain mtDNA
TK2 is one of the critical nuclear-encoded enzymes in the mitochondrial salvage pathways (pathways tasked with the creation of and recycling of nucleotides). TK2 converts the nucleosides deoxycytidine and thymidine into their nucleoside monophosphate derivatives by phosphorylation (addition of phosphate(s)). In their final form, called nucleoside triphosphates, nucleotides are the building blocks of mtDNA.
When TK2 is deficient, inside mitochondria is an imbalance of the nucleotide pool that is used to build mtDNA. When mtDNA is unable to replicate properly, ATP production is decreased in tissues throughout the body—especially those that have greater energy requirements, such as skeletal muscle, respiratory muscles, and facial and ocular muscles.
Genetics and inheritance
TK2d is an autosomal recessive disease. Both parents must be carriers of a mutated TK2 gene, and both must pass on a mutated copy of TK2 to their child.
The TK2 gene spans 42,410 base pairs on chromosome 16 of the nuclear DNA (nDNA). Encoded by nDNA, TK2 protein is created in the cellular cytoplasm and translocated into the mitochondrial, where it plays a critical role in maintaining mtDNA.
There are nearly 50 known mutations in the TK2 gene that may lead to a person having TK2d. These mutations are most commonly missense mutations but also include frameshift, nonsense, splice-site, and deletion mutations. To date, there are no clear genotype-phenotype correlations, but the phenotypes may be determined, in part, by the amount of residual activity of mutated enzymes.
Symptoms of TK2d are primarily myopathic, affecting skeletal muscle, breathing, and extra-ocular muscles, among others.
Manifestations in early-onset patients include motor development regression or delay, hypotonia, neck and limb weakness, respiratory difficulties, hyporeflexia, lactic acidemia, elevated serum creatine kinase (CK), and mtDNA depletion in muscle. Less common symptoms include feeding difficulty, seizures, ptosis, and cognitive impairment.
In patients who present with TK2d in adulthood, the symptoms can often be very different. In addition to muscle weakness causing proximal limb weakness, patients may experience prominent dysphagia, ptosis, chronic progressive external ophthalmoplegia, and facial weakness.
Path to diagnosis
For patients with mitochondrial disease, the path to diagnosis is frustrating and seemingly unending. Patients see, on average, more than 8 HCPs prior to receiving a diagnosis. Additionally, more than 50% of patients had previously received at least 1 diagnosis of a nonmitochondrial disease before their mitochondrial disease diagnosis.
Clinically, TK2d is challenging to diagnose, as it presents similarly to many other conditions in infancy and early childhood. It also presents with different symptoms for patients with the adult form, which was only identified and described within the past decade.
In addition to clues in the clinical presentation, various laboratory studies are helpful in diagnosing TK2d, including:
Elevated serum CK
Elevated blood lactate
Elevated liver enzymes (alanine transaminase and aspartate transaminase, but not gamma-glutamyl transaminase)
Electromyography (EMG) showing myogenic abnormalities
Skeletal muscle pathology, revealing ragged red fibers and cytochrome-c oxidase (COX) deficient fibers (requires muscle biopsy)
mtDNA copy number
Electron transport chain defects (particularly reduced activities of complexes I, III, and IV with sparing of complex II activity)
Diagnosis is confirmed by the identification of a pathogenic variant via genetic testing. There are various genetic testing methods that can be used, including:
Single-gene test or multigene panel test
Comprehensive genomic testing
Exome sequencing or genomic sequencing
The method utilized depends upon how much clinical and diagnostic information is available to support a suspected diagnosis of TK2d.
Other conditions that may present similarly to TK2d and should also be suspected include:
Spinal muscular atrophy (SMA)
Other mitochondrial depletion syndromes
Prader-Willi syndrome (PWS)
Congenital myasthenic syndrome
Limb-girdle muscular dystrophy
Fascioscapulohumeral dystrophy (in adults)
There are currently no FDA-approved treatments for TK2d. Treatment is primarily supportive, and focus should be placed on walking, breathing, feeding, growth, hearing, and neurological symptoms.
Some patients may require a gastrostomy or nasogastric tube in order to eat. When lung function decreases, mechanical ventilation may be required. Further, as the skeletal muscles are the primary muscles affected, physical therapy may be required to strengthen the muscles. Many patients have difficulty walking or climbing stairs and require the use of a walking aid or wheelchair.
Management of TK2d requires a multidisciplinary team of HCPs in order to provide the best possible life for the patient and delay the onset of additional symptoms. This team may include a neurologist, pulmonologist, gastroenterologist, physical therapist, clinical geneticist, and genetic counselor.
Ultimately, TK2d affects people differently based on when they initially present with symptoms. For those with the early-onset form, particularly those who present in infancy, mechanical ventilation is required in order to breathe. These patients commonly experience lung infections, which are the primary cause of death among early-onset TK2d patients. Older-presenting children tend to progress more slowly; however, the outcomes are similar in that death is caused by respiratory failure. The adult form allows patients to live with a higher quality of life with prognosis being more difficult to predict.
The Need For Information
Right now, we are just beginning to learn about and understand the impact of TK2d. But we are making progress. The HCP registry is an important tool that may help all of us work toward improving diagnosis and potential treatments for TK2 deficiency.
If you have patients with TK2d, mitochondrial DNA depletion, multiple deletion disorders, or inborn errors of metabolism, joining the registry will help keep you informed of ongoing and future research, potential therapeutic developments, and opportunities for your patients to participate in important clinical trials. Please encourage your patients to enroll in the patient registry, as they can become part of a community focused on TK2d awareness and information.
Please consider joining the HCP registry and help us take on TK2d. To sign up, or to learn more about the HCP registry, click HERE.