Infantile TK2 Deficiency Causing Mitochondrial Encephalomyopathy With Migrating Focal Seizures

Objective: Recessive variants in the TK2 gene cause thymidine kinase 2 deficiency (TK2d) presenting with infantile, childhood, or adult-onset myopathy. CNS involvement is reported in only 25% of the infantile form. Compassionate use of deoxynucleoside substrate enhancement therapy (dC/dT) has been demonstrated safe and effective in TK2d myopathy, but no data are available on the potential efficacy on the human brain disease. Methods: Here, we report for the first time a patient with infantile TK2d epileptic encephalomyopathy enrolled in an early access program with dC/dT treatment (MT1621). Results: At age 3 months, he presented progressive hypotonia, motor regression, failure to thrive, and respiratory failure. At age 8 months, he developed drug-resistant epilepsy with migrating focal seizures. Brain MRI showed progressive atrophy and bilateral subcortical lesions with lactate peak. Exome sequencing revealed 2 novel biallelic heterozygous variants in the TK2 gene (c.182G>A, p.Ser61Asn, c.704 T>C, p.Ile235Thr) whose pathogenicity was confirmed with in vitro studies. Early access compassionate use of dC/dT at 400 mg/kg prolonged the survival and stabilized the muscle disease but was not effective on the brain. Discussion: Our report highlights the importance of deep-phenotyping infantile TK2d before dC/dT supplementation to stratify disease severity further and suggests a limited tissue-specific brain efficacy.