Thymidine Kinase 2 Deficiency

checkorphan

Synonyms

TK2d, mitochondrial DNA depletion syndrome 2, MTDPS2, mitochondrial DNA depletion myopathy - TK2-related, TK2-related mitochondrial DNA maintenance defect,

Overview

Thymidine kinase 2 deficiency (TK2D) is a rare genetic mitochondrial disorder causing progressive muscle weakness (myopathy) that can lead to severe breathing, swallowing, and walking difficulties. It is caused by mutations in the TK2 gene, which disrupts the production of mitochondrial DNA (mtDNA) and impairs energy production in cells, particularly muscles. Symptoms range from mild to severe and can appear at any age, with earlier onset typically resulting in more rapid progression. 

Symptoms

Symptoms of thymidine kinase 2 (TK2) deficiency are primarily related to progressive muscle weakness and can include limb weakness, trouble breathing, swallowing, and chewing, and drooping eyelids. The severity and age of onset vary widely among individuals, and other symptoms like hearing loss and seizures can also occur. 
Muscle-related symptoms
  • Progressive muscle weakness: This is the primary symptom and can affect limbs, the trunk, and facial muscles.
  • Difficulty with motor skills: As the weakness progresses, individuals may lose the ability to walk, eat, or talk independently.
  • Drooping eyelids (ptosis): Weakness in the muscles that control the eyes can cause the eyelids to droop.
  • Eye movement problems: Difficulty or inability to move the eyes can occur due to weakness in the eye muscles. 
Breathing and swallowing symptoms 
  • Breathing difficulties: Weakness of the respiratory muscles can lead to breathing problems and, in severe cases, the need for mechanical ventilation.
  • Difficulty chewing and swallowing: Weakness in the facial muscles can make chewing and swallowing difficult. 
Other symptoms
  • Hearing loss: Sensorineural hearing loss is possible, often caused by nerve damage.
  • Seizures: An increased risk of seizures is associated with the condition, particularly in early-onset cases.
  • Cognitive and developmental issues: Some infants with the disorder may experience developmental delays, learning difficulties, or an encephalopathy.
  • Poor reflexes: Reflexes may be diminished in affected individuals.

Causes

Thymidine kinase 2 (TK2) deficiency is caused by autosomal recessive mutations in the TK2 gene, which means a person must inherit a faulty copy of the gene from both parents. These mutations lead to a deficiency of the TK2 enzyme, which is essential for the production and maintenance of mitochondrial DNA (mtDNA), causing a depletion of mtDNA and leading to progressive muscle weakness and other symptoms. 

Prevention

There is no known cure for Thymidine Kinase 2 (TK2) deficiency, so prevention of the condition itself is not possible because it is a genetic disorder. However, you can prevent the progression and manage the symptoms through a combination of supportive care, lifestyle management, and potential future treatments. 

Diagnosis

Diagnosis of thymidine kinase 2 deficiency (TK2d) involves a combination of genetic testing to identify mutations in the TK2 gene, muscle biopsy to assess mitochondrial DNA levels and muscle fibers, and clinical evaluation to assess muscle strength and function. Blood tests to check for elevated creatine kinase and lactate levels, and electrophysiology tests like EMG can also support the diagnosis. 

Prognosis

The prognosis for thymidine kinase 2 deficiency (TK2d) varies significantly based on the age of onset. Infantile-onset TK2d is typically rapid and can lead to death within 1-2 years. Childhood-onset is generally associated with survival for at least 13 years after symptoms begin, while late-onset has the longest survival, with individuals living for an average of 23 years after symptom onset. 

Treatment

The first FDA-approved treatment for TK2 deficiency, Kygevvi® (doxecitine and doxribtimine), has recently been approved and works by targeting the underlying cause of the disease. Before this approval, treatments focused on managing symptoms, which can include physical therapy, respiratory support, feeding tubes, and medications for seizures.