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Announcer: 
You’re listening to NeuroFrontiers on ReachMD, and this episode is supported by UCB. Here’s your host, Dr. Charles Turck. 

Dr. Turck: 
Welcome to NeuroFrontiers on ReachMD. I’m Dr. Charles Turck, and joining me to discuss mitochondrial diseases and strategies to improve early detection of thymidine kinase 2 deficiency, or TK2d for short, is Dr. Austin Larson. Dr. Larson is an Assistant Professor in the Section of Genetics and Metabolism within the Department of Pediatrics at the University of Colorado School of Medicine, and he practices at Children’s Hospital of Colorado where he specializes in treating patients with mitochondrial disease and genetic testing. Dr. Larson, thanks for being here today. 

Dr. Larson:
Thanks for having me. 

Dr. Turck: 
Let’s dive right in, Dr. Larson. What are some common myopathic and respiratory symptoms of TK2d?

Dr. Larson: 
TK2d is a genetic condition. It is a gene that encodes an enzyme called thymidine kinase, which is responsible for the maintenance of nucleoside pools that allow the mitochondria to replicate their DNA. So if that enzyme is not functioning, then the nucleoside pools get imbalanced, and as a result of the imbalance of the nucleoside pools, the mitochondria are unable to replicate their DNA. So in the process of depletion of mitochondrial DNA, the cells, particularly muscle cells, lose mitochondrial function. So over time, that leads to cell dysfunction and cell death. For kids with this genetic disease, that manifests as progressive weakness and loss of gross motor milestones. The muscle weakness leads to respiratory insufficiency and difficulty feeding as well. 

Dr. Turck: 
Could you tell us about any other clinical manifestations and lab tests that aid in the diagnosis of TK2d in patients?

Dr. Larson: 
For patients that are severely affected, they may have symptoms related to the central nervous system as well. So that can include seizures, encephalopathy, and hearing loss. For a child that is presenting with progressive weakness, often those children will be evaluated by a neuromuscular neurologist. They may have functional evaluations as well as lab evaluations done. So some of the things that would indicate a potential suspicion for TK2, although they’re not specific for TK2d in and of themselves, would be an elevation in creatinine kinase as well as an elevation in lactic acid. If the child had a functional evaluation from a neuromuscular perspective, it would show a myopathic electrical signature on EMG and nerve conduction studies. 

Dr. Turck: 
And are children susceptible to lactic acidosis?

Dr. Larson: 
They are. Yeah. So the mechanism of this disease is an inability to replicate the mitochondrial DNA, causing progressive mitochondrial dysfunction. If the mitochondria are not functioning, you lose the capacity for oxidative phosphorylation or aerobic cellular respiration. So that leads to a use of anaerobic cellular respiration through glycolysis, and the byproduct of that is an increase in lactic acid. So lactic acid may be elevated in kids with TK2d as well as kids with other mitochondrial disorders. 

Dr. Turck: 
For those just tuning in, you’re listening to NeuroFrontiers on ReachMD. I’m Dr. Charles Turck, and I’m speaking with Dr. Austin Larson about a myopathic form of mitochondrial disease called thymidine kinase 2 deficiency, or TK2d. 

So now that we’re more familiar with common symptoms and the diagnosis of TK2d, Dr. Larson, why is genetic testing using next-generation sequencing important to confirm a TK2d diagnosis? 

Dr. Larson: 
So everything that we talked about so far is nonspecific. An elevation in creatine kinase, an elevation in lactic acid, progressive weakness, even a myopathic signature from electromyography—none of those things would allow you to arrive at a definitive etiological diagnosis. Having a definitive etiological diagnosis is critical because understanding the mechanism of disease allows you to use a disease-modifying therapy if one is available. So the only way to arrive at a definitive mechanistic or even etiological diagnosis would be to identify the mutations in the TK2 gene that would then allow you to definitively conclude that that is the disease that the patient has. 

Dr. Turck: 
And what are some strategies that we can use to reduce diagnostic delays and detect TK2d earlier?

Dr. Larson: 
The primary strategy would be to use genetic testing earlier in the diagnostic evaluation. So I would say it would be appropriate to use genetic testing as early as the initial suspicion of progressive muscle weakness, even before identifying an elevated CK or an elevated lactic level or doing EMG or other studies. If it’s clear that a child has significant gross motor delay, and especially if it’s seeming progressive, that would be the time to use genetic testing in my opinion. And that is becoming more and more accessible and easier and easier to use. Insurance coverage of genetic testing has been a barrier in the past, however, at this point, there are several programs that sponsor genetic testing for kids with myopathic symptoms. The sample type that we use for genetic testing now is usually a buccal swab, so it doesn’t even require a blood draw or, in particular, it doesn’t require muscle biopsy. Both of which can be invasive to some degree. And the turnaround time has gotten much quicker for genetic testing than it has been in the past. So most labs would have a turnaround time for a panel that includes TK2 somewhere around the order of a few weeks. So all of those things have converged to lead me to recommend that genetic testing really should move earlier in the diagnostic evaluation of most kids with a concern for myopathy. 

Dr. Turck: 
Now if we suspect a patient of ours has TK2d, how can we ensure we’re referring them to an appropriate specialist?

Dr. Larson: 
So specialists that might be familiar with TK2d would include metabolic geneticists like myself. In addition to people in my field, many neurologists, and in particular, neuromuscular specialists would also have a familiarity with TK2d. So identifying metabolic geneticists can be found often at academic pediatric medical centers. 

There is a program called the Mitochondrial Care Network, which evaluates clinics that care for patients with mitochondrial disease to provide a centralized repository for information about those clinics. In addition to that, there’s a similar process for evaluating MDA, or Muscular Dystrophy Association Clinics, which is a good place to find a neuromuscular neurologist as well. 

Dr. Turck: 
Now before we close, Dr. Larson, do you have any final thoughts about TK2d that you’d like to leave with our audience?

Dr. Larson: 
Well, I would say that a lot of pediatric genetic diseases are not treatable. TK2d has the potential for disease-modifying treatment, and that makes it more important to identify it early in the course of disease and to make sure that the diagnostic testing that you’re using is sensitive for TK2d because it does have a disease-modifying treatment and the implementation of that treatment is time sensitive. So the takeaway that I’d like to leave people with is to recognize that genetic testing is much more user-friendly than it has been in the past. It’s non-invasive, there shouldn’t be any financial barriers, and the turnaround time with genetic testing is much quicker than it has been in the past. So for all those reasons, I would recommend using genetic testing early in the process of evaluation of any child who appears to have myopathy. 

Dr. Turck: 
Well this has been such a great discussion, and I want to thank my guest, Dr. Austin Larson, for joining me to share his insights on thymidine kinase 2 deficiency. Dr. Larson, it was a pleasure having you on the program. 

Dr. Larson: 
Thank you. I enjoyed it. 

Announcer:
This episode of NeuroFrontiers was supported by UCB. To access this and other episodes in this series, visit NeuroFrontiers on ReachMD.com, where you can Be Part of the Knowledge. Thanks for listening!