Prevalence Estimation of Thymidine Kinase 2 Deficiency: An Ultra-Rare Autosomal Recessive Mitochondrial Disease

OBJECTIVES: Thymidine kinase 2 deficiency (TK2d) is an ultra-rare mitochondrial disease characterized by premature death and substantial morbidity for which prevalence is unknown. The aim of this study was to estimate the worldwide prevalence of TK2d.

METHODS: Since data on TK2d prevalence are limited and narrow in scope, an indirect approach was utilized to generate an estimate. This involved a 3-step process: a literature search to identify sources reporting disease prevalence, ranking of the results to qualify robustness, and lastly a statistical meta-analysis. Ranking the studies into high/medium/low tiers ensured the prevalence rate was weighted more heavily toward comprehensive papers that utilized robust methods. A funnel approach was used to first estimate prevalence of patients with genetically confirmed mitochondrial disease, followed by the percentage of those with mitochondrial DNA depletion and deletion disorders (MDDS), and then the percentage of those patients with TK2d. Outputs from each sub-population were used to calculate the prevalence of TK2d.

RESULTS: The literature search revealed 7 sources reporting prevalence for mitochondrial disease; subsequently, 5 and 8 sources reported percentages of MDDS and TK2d, respectively. After the papers were ranked into tiers, Monte Carlo simulations were performed to calculate prevalence. A prevalence of ~8.92/100,000 was determined for mitochondrial disease; of these 23% were estimated to be caused by MDDS and of the MDDS, approximately 8% were caused by TK2d. These meta-analysis results suggest a TK2d prevalence of 1.64/1 million worldwide.

CONCLUSIONS: This analysis provides an up-to-date estimated prevalence of TK2d, higher than earlier reports estimating <1/1 million worldwide. True prevalence may be higher if “population at risk” of mitochondrial disease is considered, which would include all individuals with pathogenic mutations. These results emphasize the need to increase healthcare professional awareness, support earlier patient diagnosis, and the development of clear referral guidelines for this progressive, debilitating and often life-threatening disease.