Differential Diagnosis of TK2d

TK2d has overlapping phenotypes with many neuromuscular disorders and mitochondrial myopathies and is commonly misdiagnosed1,2

Historically, the diagnostic journey has been lengthy and required many tests before a conclusion was made.3

A patient with TK2d diagnosis on average has seen 8 different clinicians.3 

Even those diagnosed as adults may have early-onset TK2d if their symptoms began at or before 12 years of age.1,4

TK2d can be difficult to recognize due to its overlap with other neuromuscular disorders5,6

In this short video, Dr. Michio Hirano, Professor of Neurology and Chief of Neuromuscular Medicine at Columbia University, highlights key diagnostic challenges, common misdiagnoses, and the essential role of genetic testing.

Video Transcript

Dr Hirano video about What is TK2d

TK2d shares symptoms with a number of other diseases1,2,7

Some of these common misdiagnoses include: 

  • Pompe disease

  • Muscular dystrophy

  • Spinal muscular atrophy

  • Congenital myopathies

  • Limb-girdle muscular dystrophy

If you are considering any of these diagnoses in your patients, consider adding TK2d to your list as well.

A TK2d diagnosis is based on symptoms, patient history, clinical exams, and both laboratory and genetic tests7

Diagnostic workup for TK2d may include:

Clinical evaluation3,7-9

  • Patient history

  • Physical exam

  • Symptom assessment

Laboratory findings1

  • Elevated creatine kinase

  • Transient liver enzyme elevations (ALT, AST, GGT, bilirubin)

  • Lactic acidemia

  • Elevated alkaline phosphatase

Muscle biopsy and tissue testing1,2,10,11

  • Reduced mitochondrial DNA content or multiple deletion

  • Atrophic and/or necrotic fibers

  • Fiber size variability/Type 1 predominance

  • Cox-deficient fibers

  • Ragged-red fibres

  • Typically Cox-deficient and Succinate dehydrogenase (SDH) activity is increased

  • OXPHOS deficits (multiple or single enzyme abnormalities)

 

Muscle MRI patterns8,12

  • Early and pronounced involvement of the sartorius muscle

Biomarkers1,5

  • GDF-15

  • FGF-21 (under investigation)

If there is multisystemic involvement9

  • Length-dependent axonal sensory-motor neuropathy

Other tests to consider for diagnosing TK2d
mtDNA analysis icon

mtDNA analysis10

  • Real-time polymerase chain reaction test used to analyse mtDNA content (copy number)

EMG/Nerve conduction studies icon

EMG/Nerve conduction studies (NCSs)13

  • Helps detect myopathic changes/abnormalities

  • Many patients with a mitochondrial myopathy, such as TK2d, may have normal or nonspecific changes to EMG studies

    • Some patients with TK2d (78.6%, 33/42) showed myopathic changes on EMG and NCS, including polyphasic short‑duration low‑amplitude motor unit potentials11

  • Not specific and not a confirmatory diagnostic test

 

Blood and biochemical icon

Blood and biochemical9,14

  • Can include blood lactate, pyruvate, serum creatine kinase, and many more

  • Requires caution when interpreting findings, as any alterations identified will not be specific to a mitochondrial disease, such as TK2d. Findings are not typically diagnostic and warrant additional testing

  • Results can raise suspicion of mitochondrial dysfunction

 

Muscle biopsy icon

Muscle biopsy1-3,10,11

  • A muscle biopsy may reveal the presence of ragged red fibers, COX-deficient fibers, and mtDNA depletion or deletion

  • Can be painful and invasive

  • Previously considered the gold standard, but is not always highly sensitive or specific about a particular mitochondrial disease, such as TK2d

  • Recommended when an mtDNA depletion or deletion syndrome, such as TK2d, is suspected

MRI icon

MRI10,12

  • Mitochondrial diseases, such as TK2d, produce variable imaging abnormalities in various muscles, and some patterns can be very helpful in diagnosis

  • May or may not show structural alterations depending on the type of mitochondrial diseases and type of central nervous system involvement

  • Not definitive for a diagnosis

Panel test icon

Reanalysis of a panel test or WGS/WES15

  • WGS/WES testing process reanalysis can be beneficial to improve diagnostic sensitivity, given the patient’s symptoms and medical/family history

  • A reanalysis could identify newly published variants from the time of last analysis

     

Genetic testing inclusive of mitochondrial genes, including TK2, is the most direct path to diagnosis.2,16

 

A direct path to diagnosis is possible by recognising the red flag symptoms of TK2d and recommending genetic testing16

A genetic test should be inclusive of the TK2 gene. If patients experience mitochondrial disease symptoms and have undergone prior tests that did not include the TK2 gene, it’s important to retest or reanalyse the sample.1-3,5,16

Find out more

Learn About Genetic Testing

Genetic testing provides a definitive diagnosis of TK2d.10

See test options

Sign Up for More Information

Receive information from UCB about developments in TK2d and other mitochondrial diseases.

Stay connected