TK2D Muscle Biopsy and Genetic Testing Strategy: Panel or Exome

In "TK2D Muscle Biopsy and Genetic Testing Strategy: Panel or Exome," our experts turn to the role of tissue evidence and the choice among tests.

Dr. Hirano asks whether she would take a muscle biopsy before genetic testing, as in Case 1. Dr. Zolkipli-Cunningham says most centers consider genetic testing first-line, but as a neuromuscular physician she likes biopsies because they can show a respiratory chain defect and mitochondrial DNA depletion that aligns with TK2 variants. The decision depends on the provider, institution, and patient. Families may hesitate to intubate a floppy infant for an open biopsy, while older children and adults can undergo it quickly. A biopsy without depletion does not exclude TK2D, because depletion depends on disease phase. Before genetic testing, she saw patients who lacked depletion at first biopsy but showed it on repeat. Evaluation should involve specialists who see these patients regularly.

For variants of uncertain significance, the diagnosis is not confirmed. Because muscle is affected and accessible, a respiratory chain defect with low mitochondrial DNA content provides functional support.

Dr. Hirano asks about the differential and test choice. She says her institution rarely uses single-gene sequencing, although it suits conditions such as spinal muscular atrophy. Access is the biggest driver. Starting with a panel and moving to exome is acceptable, but stopping after a less comprehensive test is not. Spinal muscular atrophy, congenital myopathy, myasthenia gravis, and neurodegenerative disorders must be considered, and cultural and religious factors require counseling. Dr. Hirano adds that treatable conditions such as spinal muscular atrophy, TK2D, and Pompe disease can resemble one another, which argues for a wider net. Dr. Zolkipli-Cunningham raises the time factor, since a panel followed by an exome could cost six months while earlier treatment appears to help more. She considers whole exome first-line in the United States.

In "Beyond Supportive Care: Nucleoside Therapy Mechanism and Outcomes in TK2D," the panel explores what supportive care cannot do and then reviews the first approved disease-modifying therapy.