Infantile TK2 Deficiency Causing Mitochondrial Encephalomyopathy With Migrating Focal Seizures.

Area of Science:

• Genetics and Neurology
• Mitochondrial Diseases
• Rare Pediatric Neurological Disorders

Background:

• Recessive variants in the thymidine kinase 2 (TK2) gene cause thymidine kinase 2 deficiency (TK2d), a myopathy with variable onset.
• Central nervous system (CNS) involvement is infrequent in the infantile form of TK2d.
• Deoxynucleoside substrate enhancement therapy (dC/dT) has shown promise for TK2d myopathy, but its effect on CNS disease is unknown.

Purpose of the Study:

• To report the first case of infantile TK2d epileptic encephalomyopathy treated with dC/dT under an early access program.
• To evaluate the efficacy of dC/dT on neurological manifestations in infantile TK2d.
• To investigate the genetic basis and clinical course of infantile TK2d with CNS involvement.

Main Methods:

• A patient with infantile TK2d epileptic encephalomyopathy was enrolled in an early access program for dC/dT treatment (MT1621).
• Clinical presentation, including hypotonia, motor regression, failure to thrive, respiratory failure, and drug-resistant epilepsy, was documented.
• Exome sequencing identified novel biallelic heterozygous variants in the TK2 gene, with pathogenicity confirmed in vitro.
• Brain MRI was used to assess CNS involvement, including atrophy and subcortical lesions.

Main Results:

• The patient presented with progressive hypotonia, motor regression, failure to thrive, and respiratory failure at 3 months.
• Drug-resistant epilepsy with migrating focal seizures developed at 8 months.
• Brain MRI revealed progressive atrophy and bilateral subcortical lesions with a lactate peak.
• Genetic analysis identified two novel heterozygous variants in the TK2 gene: c.182G>A (p.Ser61Asn) and c.704T>C (p.Ile235Thr).
• dC/dT treatment prolonged survival and stabilized muscle disease but did not improve neurological symptoms or CNS lesions.

Conclusions:

• This case highlights the importance of comprehensive phenotyping in infantile TK2d to accurately assess disease severity prior to dC/dT supplementation.
• The findings suggest that dC/dT may have limited efficacy in treating the brain manifestations of infantile TK2d.
• Further research is needed to understand tissue-specific responses to dC/dT therapy in mitochondrial disorders.