Infantile TK2 Deficiency Causing Mitochondrial Encephalomyopathy With Migrating Focal Seizures

Abstract

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.

Figure 1. Functional Studies Confirming the Pathogenicity of the TK2 Gene Variants

(A) TK2 gene expression revealing severe reduction in the patient (n = 2 biological replicates) compared with healthy control (n = 2 biological replicates), (B and C) mtDNA copy number in DNA extracted from muscle homogenates (B) and fibroblast cell line (C) showing severe reduction in the patient (n = 1 biological replicates in muscle, 2 in fibroblast) compared with the healthy control (CTRL, n = 1 biological replicates in muscle, 2 in fibroblast). Data derived from at least 3 independent experiments. All data are expressed as a percentage of control and presented as mean ± SEM. ***p < 0.001, ****p < 0.0001.

Figure 2. EEG Pattern During Continuous Video-EEG Monitoring

(A) Ictal EEG at 8 months showing focal seizures migrating from the right to the left hemisphere (black arrows, 90 seconds/page), (B and C) follow-up at age 10 months showing progressive EEG worsening with disruption of background activity, burst suppression pattern (B: 30 seconds/page), and subcontinuous migrating focal seizures (black arrows, C: 60 seconds/page).

Figure 3. Brain MRI Study

(A–D) T2-weighted images showing high-intensity signal in the insular and postcentral gyrus areas and sub/cortical atrophy at 8 months, (E–H) follow-up study at 10 months showing severe worsening of signal alterations over time, with spread to the basal ganglia, temporo-occipital and frontal regions and progression of the sub/cortical atrophy over time.